%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Shayna Stein, Rui Zhao, Hiroshi Haeno, Igor Vivanco, Franziska Michor
Mathematical modeling identifies optimum lapatinib dosing schedules for the treatment of glioblastoma patients
www.ploscompbiol.org
www.ploscompbiol.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 13 0 R/Contents 14 0 R/TrimBox[0 0 612 792]>>
endobj
13 0 obj
[15 0 R 16 0 R 17 0 R 18 0 R 19 0 R 20 0 R 21 0 R 22 0 R 23 0 R 24 0 R 25 0 R 26 0 R 27 0 R 28 0 R 29 0 R 30 0 R 31 0 R 32 0 R 33 0 R 34 0 R 35 0 R 36 0 R 37 0 R 38 0 R]
endobj
15 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref001)>>
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref002)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.t001)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref003)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref004)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref005)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref006)>>
endobj
22 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref014)>>
endobj
23 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref015)>>
endobj
24 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref016)>>
endobj
25 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref015)>>
endobj
26 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref016)>>
endobj
27 0 obj
<>/Border[0 0 0]/Dest(Lpcbi.1005924.t001)>>
endobj
28 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref077)>>
endobj
29 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref078)>>
endobj
30 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref079)>>
endobj
31 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref080)>>
endobj
32 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref081)>>
endobj
33 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref082)>>
endobj
34 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref015)>>
endobj
35 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref016)>>
endobj
36 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref017)>>
endobj
37 0 obj
<>/Border[0 0 0]/A 39 0 R>>
endobj
39 0 obj
<>
endobj
38 0 obj
<>/Border[0 0 0]/A 40 0 R>>
endobj
40 0 obj
<>
endobj
14 0 obj
[41 0 R 42 0 R 43 0 R 44 0 R 45 0 R 46 0 R 47 0 R 48 0 R 49 0 R 50 0 R 51 0 R 52 0 R 53 0 R 54 0 R 55 0 R 56 0 R 57 0 R 58 0 R 59 0 R 60 0 R]
endobj
41 0 obj
<>stream
q
0.955 g
0 w
199.9998 713.9999 m
575.9997 713.9999 l
575.9997 585.0003 l
199.9998 585.0003 l
f*
0.83 0.64 0.02 0 k
406.9984 508.8189 m
411.7606 508.8189 l
h
f*
263.1685 482.7969 m
267.9307 482.7969 l
h
f*
378.652 417.7701 m
407.8488 417.7701 l
h
f*
384.2646 391.8047 m
389.0268 391.8047 l
h
f*
393.4488 391.8047 m
398.211 391.8047 l
h
f*
529.7953 313.7953 m
534.5575 313.7953 l
h
f*
326.5512 300.8126 m
331.3134 300.8126 l
h
f*
336.4724 300.8126 m
345.9969 300.8126 l
h
f*
203.4142 287.7732 m
212.9386 287.7732 l
h
f*
217.3606 287.7732 m
226.885 287.7732 l
h
f*
218.4378 274.7906 m
227.9055 274.7906 l
h
f*
232.3843 274.7906 m
241.9087 274.7906 l
h
f*
0 g
1 j
1 J
10 0 0 10 209.9905 696.9826 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(the)Tj
1.4683 0 Td
(maximum)Tj
4.3767 0 Td
(tolerated)Tj
3.7473 0 Td
(dose,)Tj
2.2677 0 Td
(pharmacokinetics)Tj
7.336 0 Td
(and)Tj
1.7348 0 Td
(pharmacodynamics)Tj
8.0901 0 Td
(profiles.)Tj
3.4242 0 Td
(We)Tj
-32.4451 -1.2982 Td
(present)Tj
3.1634 0 Td
(a)Tj
0.6576 0 Td
(computational)Tj
6.0435 0 Td
(modeling)Tj
4.0251 0 Td
(platform)Tj
3.7021 0 Td
(incorporating)Tj
5.7486 0 Td
(both)Tj
2.0579 0 Td
(in)Tj
1.0375 0 Td
(vitro)Tj
2.1203 0 Td
(data)Tj
1.9105 0 Td
(and)Tj
1.7292 0 Td
(pub-)Tj
-32.1957 -1.2983 Td
(lished)Tj
2.5738 0 Td
(clinical)Tj
3.0784 0 Td
(trial)Tj
1.8368 0 Td
(data)Tj
1.9106 0 Td
(to)Tj
1.0261 0 Td
(investigate)Tj
4.4617 0 Td
(the)Tj
1.4684 0 Td
(efficacy)Tj
3.2258 0 Td
(of)Tj
1.0148 0 Td
(lapatinib)Tj
3.736 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.6576 0 Td
(function)Tj
3.6283 0 Td
(of)Tj
1.0148 0 Td
(different)Tj
-30.6479 -1.3039 Td
(dosing)Tj
2.8969 0 Td
(schedules)Tj
4.0422 0 Td
(for)Tj
1.389 0 Td
(inhibiting)Tj
4.1782 0 Td
(glioblastoma)Tj
5.3178 0 Td
(tumor)Tj
2.7439 0 Td
(cell)Tj
1.5591 0 Td
(growth.)Tj
3.2995 0 Td
(The)Tj
1.7801 0 Td
(goal)Tj
1.8709 0 Td
(of)Tj
1.0148 0 Td
(our)Tj
1.627 0 Td
(method)Tj
-31.7194 -1.2983 Td
(is)Tj
0.8503 0 Td
(to)Tj
1.0262 0 Td
(find)Tj
1.8482 0 Td
(the)Tj
1.4683 0 Td
(best)Tj
1.8141 0 Td
(dosing)Tj
2.8914 0 Td
(schedule)Tj
3.685 0 Td
(balancing)Tj
4.0932 0 Td
(both)Tj
2.0579 0 Td
(toxicity)Tj
3.2032 0 Td
(and)Tj
1.7291 0 Td
(efficacy.)Tj
3.4469 0 Td
(Our)Tj
1.8652 0 Td
(modeling)Tj
-29.979 -1.2982 Td
(approach)Tj
3.9514 0 Td
(identifies)Tj
3.8948 0 Td
(continuous)Tj
4.7338 0 Td
(dosing)Tj
2.897 0 Td
(as)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(best)Tj
1.8141 0 Td
(clinically)Tj
3.7757 0 Td
(feasible)Tj
3.1692 0 Td
(strategy)Tj
3.3278 0 Td
(for)Tj
1.3833 0 Td
(slowing)Tj
-31.4303 -1.3039 Td
(down)Tj
2.4888 0 Td
(tumor)Tj
2.7439 0 Td
(growth)Tj
3.0727 0 Td
(even)Tj
2.0693 0 Td
(when)Tj
2.4038 0 Td
(taking)Tj
2.7325 0 Td
(into)Tj
1.8425 0 Td
(consideration)Tj
5.7033 0 Td
(intratumor)Tj
4.6601 0 Td
(heterogeneity,)Tj
-27.7169 -1.2983 Td
(drug)Tj
2.1146 0 Td
(resistance)Tj
4.1329 0 Td
(and)Tj
1.7291 0 Td
(reduced)Tj
3.4412 0 Td
(lapatinib)Tj
3.7417 0 Td
(concentrations)Tj
6.1795 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(tumor)Tj
2.744 0 Td
(due)Tj
1.7007 0 Td
(to)Tj
1.0262 0 Td
(the)Tj
1.4683 0 Td
(blood)Tj
2.5115 0 Td
(brain)Tj
-33.2955 -1.2983 Td
(barrier.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 539.8866 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Introduction)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 522.8787 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Glioblastoma)Tj
5.5615 0 Td
(is)Tj
0.8504 0 Td
(the)Tj
1.4683 0 Td
(most)Tj
2.2054 0 Td
(common)Tj
3.8437 0 Td
(and)Tj
1.7291 0 Td
(aggressive)Tj
4.2463 0 Td
(form)Tj
2.2053 0 Td
(of)Tj
1.0148 0 Td
(brain)Tj
2.3528 0 Td
(tumors)Tj
3.1011 0 Td
(in)Tj
1.0374 0 Td
(adults,)Tj
2.8403 0 Td
(character-)Tj
-32.4564 -1.2982 Td
(ized)Tj
1.8481 0 Td
(by)Tj
1.1792 0 Td
(short)Tj
2.2847 0 Td
(survival)Tj
3.3336 0 Td
(and)Tj
1.7291 0 Td
(poor)Tj
2.1203 0 Td
(treatment)Tj
4.1329 0 Td
(response)Tj
3.7303 0 Td
([)Tj
0.83 0.64 0.02 0 k
(1)Tj
0 g
(].)Tj
1.5988 0 Td
(Currently,)Tj
4.3483 0 Td
(the)Tj
1.4683 0 Td
(standard)Tj
3.7191 0 Td
(of)Tj
1.0148 0 Td
(care)Tj
1.8651 0 Td
(for)Tj
1.3833 0 Td
(glio-)Tj
-35.7559 -1.3039 Td
(blastoma)Tj
3.8267 0 Td
(patients)Tj
3.3675 0 Td
(includes)Tj
3.5433 0 Td
(surgery)Tj
3.1975 0 Td
(followed)Tj
3.651 0 Td
(by)Tj
1.1792 0 Td
(radiotherapy)Tj
5.3518 0 Td
(and)Tj
1.7348 0 Td
(adjuvant)Tj
3.702 0 Td
(chemotherapy)Tj
5.947 0 Td
(with)Tj
-35.5008 -1.2983 Td
(temozolomide)Tj
5.981 0 Td
([)Tj
0.83 0.64 0.02 0 k
(2)Tj
0 g
(].)Tj
1.5987 0 Td
(However,)Tj
4.0762 0 Td
(the)Tj
1.4684 0 Td
(addition)Tj
3.6 0 Td
(of)Tj
1.0148 0 Td
(chemotherapy)Tj
5.947 0 Td
(only)Tj
1.9786 0 Td
(modestly)Tj
3.8551 0 Td
(prolongs)Tj
3.7473 0 Td
(survival)Tj
-33.2671 -1.2983 Td
(\(median)Tj
3.5773 0 Td
(14.6)Tj
1.8765 0 Td
(months\))Tj
3.6226 0 Td
(compared)Tj
4.2406 0 Td
(to)Tj
1.0262 0 Td
(radiation)Tj
3.8721 0 Td
(alone)Tj
2.3811 0 Td
(\(median)Tj
3.5829 0 Td
(12.1)Tj
1.8709 0 Td
(months\).)Tj
3.8494 0 Td
(Thus,)Tj
2.4718 0 Td
(there)Tj
-32.3714 -1.3039 Td
(remains)Tj
3.4412 0 Td
(a)Tj
0.6576 0 Td
(pressing)Tj
3.532 0 Td
(unmet)Tj
2.8403 0 Td
(medical)Tj
3.3618 0 Td
(need)Tj
2.143 0 Td
(for)Tj
1.3833 0 Td
(more)Tj
2.3414 0 Td
(effective)Tj
3.515 0 Td
(therapeutic)Tj
4.7281 0 Td
(agents.)Tj
2.9764 0 Td
(Unfortunately,)Tj
-30.9201 -1.2982 Td
(since)Tj
2.245 0 Td
(the)Tj
1.4683 0 Td
(introduction)Tj
5.3121 0 Td
(of)Tj
1.0148 0 Td
(temozolomide,)Tj
6.2022 0 Td
(no)Tj
1.2755 0 Td
(other)Tj
2.3471 0 Td
(compound)Tj
4.6035 0 Td
(has)Tj
1.542 0 Td
(been)Tj
2.1203 0 Td
(able)Tj
1.8312 0 Td
(to)Tj
1.0261 0 Td
(significantly)Tj
-30.9881 -1.2983 Td
(prolong)Tj
3.3788 0 Td
(patient)Tj
3.0104 0 Td
(survival)Tj
3.3335 0 Td
(in)Tj
1.0375 0 Td
(clinical)Tj
3.0784 0 Td
(trials.)Tj
2.4208 0 Td
(For)Tj
1.6271 0 Td
(orally)Tj
2.4774 0 Td
(administered)Tj
5.4935 0 Td
(drugs,)Tj
2.6986 0 Td
(most)Tj
2.2053 0 Td
(trials)Tj
2.194 0 Td
(have)Tj
2.0636 0 Td
(only)Tj
-35.0189 -1.3039 Td
(explored)Tj
3.702 0 Td
(daily)Tj
2.1486 0 Td
(continuous)Tj
4.7339 0 Td
(dosing)Tj
2.8969 0 Td
(schedules)Tj
4.0422 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Table)Tj
2.7836 0 Td
(1)Tj
0 g
(\).)Tj
1.2586 0 Td
(However,)Tj
4.0762 0 Td
(there)Tj
2.2677 0 Td
(is)Tj
0.8504 0 Td
(increasing)Tj
4.3256 0 Td
(evidence)Tj
-33.0857 -1.2983 Td
(that)Tj
1.7744 0 Td
(for)Tj
1.389 0 Td
(some)Tj
2.3301 0 Td
(targeted)Tj
3.4639 0 Td
(agents,)Tj
2.9763 0 Td
(intermittent)Tj
5.0797 0 Td
(schedules)Tj
4.0422 0 Td
(can)Tj
1.627 0 Td
(deliver)Tj
2.9367 0 Td
(equal)Tj
2.3584 0 Td
(or)Tj
1.0942 0 Td
(potentially)Tj
4.4617 0 Td
(even)Tj
-33.5336 -1.2983 Td
(superior)Tj
3.5659 0 Td
(therapeutic)Tj
4.7338 0 Td
(benefit)Tj
2.9707 0 Td
(with)Tj
2.0013 0 Td
(less)Tj
1.61 0 Td
(toxicity)Tj
3.2032 0 Td
([)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2586 0 Td
(4)Tj
0 g
(].)Tj
-18.1473 -1.2982 Td
(In)Tj
1.1111 0 Td
(the)Tj
1.4684 0 Td
(last)Tj
1.559 0 Td
(decade,)Tj
3.2088 0 Td
(several)Tj
2.931 0 Td
(molecularly)Tj
4.9209 0 Td
(targeted)Tj
3.464 0 Td
(agents)Tj
2.7495 0 Td
(that)Tj
1.7802 0 Td
(inhibit)Tj
2.9026 0 Td
(recurrently)Tj
4.6772 0 Td
(mutated)Tj
3.5489 0 Td
(pro-)Tj
-35.5178 -1.3039 Td
(teins)Tj
2.1146 0 Td
(have)Tj
2.0636 0 Td
(been)Tj
2.1203 0 Td
(investigated)Tj
4.9889 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.6577 0 Td
(therapeutic)Tj
4.7281 0 Td
(strategy)Tj
3.3279 0 Td
(in)Tj
1.0375 0 Td
(glioblastoma.)Tj
5.5388 0 Td
(These)Tj
2.5625 0 Td
(have)Tj
2.0636 0 Td
(included)Tj
-32.2183 -1.2983 Td
(several)Tj
2.931 0 Td
(inhibitors)Tj
4.1442 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(epidermal)Tj
4.252 0 Td
(growth)Tj
3.0727 0 Td
(factor)Tj
2.5398 0 Td
(receptor)Tj
3.5603 0 Td
(\(EFGR\),)Tj
3.5603 0 Td
(which)Tj
2.6475 0 Td
(is)Tj
0.8504 0 Td
(mutationally)Tj
5.3008 0 Td
(acti-)Tj
-35.3421 -1.2983 Td
(vated)Tj
2.3584 0 Td
(in)Tj
1.0318 0 Td
(approximately)Tj
5.9754 0 Td
(50%)Tj
1.9332 0 Td
(of)Tj
1.0148 0 Td
(adult)Tj
2.2507 0 Td
(GBMs.)Tj
2.9933 0 Td
(Lapatinib)Tj
4.0309 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.6519 0 Td
(small)Tj
2.3301 0 Td
(molecule)Tj
3.8381 0 Td
(tyrosine)Tj
3.4526 0 Td
(kinase)Tj
-32.7116 -1.3039 Td
(inhibitor)Tj
3.7813 0 Td
(of)Tj
1.0148 0 Td
(human)Tj
3.0784 0 Td
(epidermal)Tj
4.2463 0 Td
(receptor)Tj
3.5603 0 Td
(2)Tj
0.6917 0 Td
(\(HER2\))Tj
3.3335 0 Td
(and)Tj
1.7348 0 Td
(EGFR,)Tj
2.88 0 Td
(which)Tj
2.6475 0 Td
(currently)Tj
3.8834 0 Td
(has)Tj
1.5421 0 Td
(regulatory)Tj
-32.3941 -1.2982 Td
(approval)Tj
3.702 0 Td
(for)Tj
1.3833 0 Td
(the)Tj
1.4683 0 Td
(treatment)Tj
4.1386 0 Td
(of)Tj
1.0148 0 Td
(HER2-positive)Tj
6.1001 0 Td
(advanced)Tj
3.9968 0 Td
(or)Tj
1.0942 0 Td
(metastatic)Tj
4.2803 0 Td
(breast)Tj
2.6135 0 Td
(cancer)Tj
2.846 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(].)Tj
1.5987 0 Td
(Addi-)Tj
-34.2366 -1.2983 Td
(tional)Tj
2.5171 0 Td
(indications)Tj
4.6715 0 Td
(for)Tj
1.3889 0 Td
(lapatinib)Tj
3.7361 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(14)Tj
0 g
(])Tj
2.8459 0 Td
(including)Tj
4.0422 0 Td
(glioblastoma,)Tj
5.5389 0 Td
(are)Tj
1.4456 0 Td
(currently)Tj
3.8892 0 Td
(being)Tj
2.4264 0 Td
(explored)Tj
-32.5018 -1.3039 Td
([)Tj
0.83 0.64 0.02 0 k
(15)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7347 0 Td
(16)Tj
0 g
(].)Tj
1.7348 0 Td
(In)Tj
1.1112 0 Td
(GBM,)Tj
2.6362 0 Td
(clinical)Tj
3.0727 0 Td
(trials)Tj
2.1997 0 Td
(of)Tj
1.0148 0 Td
(lapatinib)Tj
3.7361 0 Td
(have)Tj
2.0636 0 Td
(failed)Tj
2.4037 0 Td
(to)Tj
1.0262 0 Td
(show)Tj
2.3017 0 Td
(efficacy)Tj
3.2201 0 Td
(using)Tj
2.3924 0 Td
(continuous)Tj
4.7339 0 Td
(dos-)Tj
-35.3818 -1.2983 Td
(ing)Tj
1.5023 0 Td
([)Tj
0.83 0.64 0.02 0 k
(15)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.7348 0 Td
(16)Tj
0 g
(].)Tj
1.7348 0 Td
(Interestingly,)Tj
5.4935 0 Td
(a)Tj
0.652 0 Td
(study)Tj
2.3924 0 Td
(that)Tj
1.7745 0 Td
(evaluated)Tj
3.9911 0 Td
(EGFR)Tj
2.6532 0 Td
(inhibition)Tj
4.2293 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.652 0 Td
(means)Tj
2.8062 0 Td
(to)Tj
1.0262 0 Td
(prime)Tj
2.6192 0 Td
(tumor)Tj
-34.2763 -1.2983 Td
(vasculature)Tj
4.7224 0 Td
(for)Tj
1.3833 0 Td
(efficient)Tj
3.4469 0 Td
(delivery)Tj
3.3903 0 Td
(of)Tj
1.0148 0 Td
(chemotherapy)Tj
5.947 0 Td
(showed)Tj
3.2542 0 Td
(that)Tj
1.7744 0 Td
(in)Tj
1.0375 0 Td
(glioblastoma)Tj
5.3121 0 Td
(patients,)Tj
3.5943 0 Td
(a)Tj
-34.8772 -1.3039 Td
(2-day)Tj
2.4604 0 Td
(pulse)Tj
2.2961 0 Td
(of)Tj
1.0148 0 Td
(high)Tj
2.0069 0 Td
(dose)Tj
2.0409 0 Td
(\(5,250)Tj
2.6872 0 Td
(mg/day\))Tj
3.5887 0 Td
(lapatinib)Tj
3.7417 0 Td
(given)Tj
2.3811 0 Td
(through)Tj
3.4412 0 Td
(twice)Tj
2.3187 0 Td
(daily)Tj
2.1487 0 Td
(dosing)Tj
2.897 0 Td
(was)Tj
1.7007 0 Td
(well)Tj
ET
Q
q
0.45 0.36 0.35 0.01 k
1 j
1 J
0 w
35.9997 221.7634 m
575.9997 221.7634 l
575.9997 221.2634 l
35.9997 221.2634 l
f*
154.044 206.7633 m
35.9997 206.7633 l
35.9997 208.7634 l
154.044 208.7634 l
f*
154.044 221.2634 m
154.044 208.7634 l
153.544 208.7634 l
153.544 221.2634 l
f*
153.544 208.7634 m
35.9997 208.7634 l
35.9997 209.2635 l
153.544 209.2635 l
f*
247.7208 206.7633 m
154.044 206.7633 l
154.044 208.7634 l
247.7208 208.7634 l
f*
247.7208 221.2634 m
247.7208 208.7634 l
247.2208 208.7634 l
247.2208 221.2634 l
f*
247.2208 208.7634 m
154.044 208.7634 l
154.044 209.2635 l
247.2208 209.2635 l
f*
346.3946 206.7633 m
247.7208 206.7633 l
247.7208 208.7634 l
346.3946 208.7634 l
f*
346.3946 221.2634 m
346.3946 208.7634 l
345.8945 208.7634 l
345.8945 221.2634 l
f*
345.8945 208.7634 m
247.7208 208.7634 l
247.7208 209.2635 l
345.8945 209.2635 l
f*
575.9994 206.7633 m
346.3946 206.7633 l
346.3946 208.7634 l
575.9994 208.7634 l
f*
575.9994 208.7634 m
346.3946 208.7634 l
346.3946 209.2635 l
575.9994 209.2635 l
f*
154.044 206.7633 m
154.044 194.2634 l
153.544 194.2634 l
153.544 206.7633 l
f*
153.544 194.2634 m
35.9997 194.2634 l
35.9997 194.7634 l
153.544 194.7634 l
f*
247.7208 206.7633 m
247.7208 194.2634 l
247.2208 194.2634 l
247.2208 206.7633 l
f*
247.2208 194.2634 m
154.044 194.2634 l
154.044 194.7634 l
247.2208 194.7634 l
f*
346.3946 206.7633 m
346.3946 194.2634 l
345.8945 194.2634 l
345.8945 206.7633 l
f*
345.8945 194.2634 m
247.7208 194.2634 l
247.7208 194.7634 l
345.8945 194.7634 l
f*
575.9994 194.2634 m
346.3946 194.2634 l
346.3946 194.7634 l
575.9994 194.7634 l
f*
154.044 194.2634 m
154.044 181.7634 l
153.544 181.7634 l
153.544 194.2634 l
f*
153.544 181.7634 m
35.9997 181.7634 l
35.9997 182.2635 l
153.544 182.2635 l
f*
247.7208 194.2634 m
247.7208 181.7634 l
247.2208 181.7634 l
247.2208 194.2634 l
f*
247.2208 181.7634 m
154.044 181.7634 l
154.044 182.2635 l
247.2208 182.2635 l
f*
346.3946 194.2634 m
346.3946 181.7634 l
345.8945 181.7634 l
345.8945 194.2634 l
f*
345.8945 181.7634 m
247.7208 181.7634 l
247.7208 182.2635 l
345.8945 182.2635 l
f*
575.9994 181.7634 m
346.3946 181.7634 l
346.3946 182.2635 l
575.9994 182.2635 l
f*
154.044 181.7634 m
154.044 169.2635 l
153.544 169.2635 l
153.544 181.7634 l
f*
153.544 169.2635 m
35.9997 169.2635 l
35.9997 169.7635 l
153.544 169.7635 l
f*
247.7208 181.7634 m
247.7208 169.2635 l
247.2208 169.2635 l
247.2208 181.7634 l
f*
247.2208 169.2635 m
154.044 169.2635 l
154.044 169.7635 l
247.2208 169.7635 l
f*
346.3946 181.7634 m
346.3946 169.2635 l
345.8945 169.2635 l
345.8945 181.7634 l
f*
345.8945 169.2635 m
247.7208 169.2635 l
247.7208 169.7635 l
345.8945 169.7635 l
f*
575.9994 169.2635 m
346.3946 169.2635 l
346.3946 169.7635 l
575.9994 169.7635 l
f*
154.044 169.2635 m
154.044 156.7636 l
153.544 156.7636 l
153.544 169.2635 l
f*
153.544 156.7636 m
35.9997 156.7636 l
35.9997 157.2636 l
153.544 157.2636 l
f*
247.7208 169.2635 m
247.7208 156.7636 l
247.2208 156.7636 l
247.2208 169.2635 l
f*
247.2208 156.7636 m
154.044 156.7636 l
154.044 157.2636 l
247.2208 157.2636 l
f*
346.3946 169.2635 m
346.3946 156.7636 l
345.8945 156.7636 l
345.8945 169.2635 l
f*
345.8945 156.7636 m
247.7208 156.7636 l
247.7208 157.2636 l
345.8945 157.2636 l
f*
575.9994 156.7636 m
346.3946 156.7636 l
346.3946 157.2636 l
575.9994 157.2636 l
f*
154.044 156.7636 m
154.044 144.2636 l
153.544 144.2636 l
153.544 156.7636 l
f*
153.544 144.2636 m
35.9997 144.2636 l
35.9997 144.7637 l
153.544 144.7637 l
f*
247.7208 156.7636 m
247.7208 144.2636 l
247.2208 144.2636 l
247.2208 156.7636 l
f*
247.2208 144.2636 m
154.044 144.2636 l
154.044 144.7637 l
247.2208 144.7637 l
f*
346.3946 156.7636 m
346.3946 144.2636 l
345.8945 144.2636 l
345.8945 156.7636 l
f*
345.8945 144.2636 m
247.7208 144.2636 l
247.7208 144.7637 l
345.8945 144.7637 l
f*
575.9994 144.2636 m
346.3946 144.2636 l
346.3946 144.7637 l
575.9994 144.7637 l
f*
154.044 144.2636 m
154.044 131.7637 l
153.544 131.7637 l
153.544 144.2636 l
f*
153.544 131.7637 m
35.9997 131.7637 l
35.9997 132.2637 l
153.544 132.2637 l
f*
247.7208 144.2636 m
247.7208 131.7637 l
247.2208 131.7637 l
247.2208 144.2636 l
f*
247.2208 131.7637 m
154.044 131.7637 l
154.044 132.2637 l
247.2208 132.2637 l
f*
346.3946 144.2636 m
346.3946 131.7637 l
345.8945 131.7637 l
345.8945 144.2636 l
f*
345.8945 131.7637 m
247.7208 131.7637 l
247.7208 132.2637 l
345.8945 132.2637 l
f*
575.9994 131.7637 m
346.3946 131.7637 l
346.3946 132.2637 l
575.9994 132.2637 l
f*
154.044 131.7637 m
154.044 119.2637 l
153.544 119.2637 l
153.544 131.7637 l
f*
153.544 119.2637 m
35.9997 119.2637 l
35.9997 119.7638 l
153.544 119.7638 l
f*
247.7208 131.7637 m
247.7208 119.2637 l
247.2208 119.2637 l
247.2208 131.7637 l
f*
247.2208 119.2637 m
154.044 119.2637 l
154.044 119.7638 l
247.2208 119.7638 l
f*
346.3946 131.7637 m
346.3946 119.2637 l
345.8945 119.2637 l
345.8945 131.7637 l
f*
345.8945 119.2637 m
247.7208 119.2637 l
247.7208 119.7638 l
345.8945 119.7638 l
f*
575.9994 119.2637 m
346.3946 119.2637 l
346.3946 119.7638 l
575.9994 119.7638 l
f*
154.044 119.2637 m
154.044 106.7638 l
153.544 106.7638 l
153.544 119.2637 l
f*
153.544 106.7638 m
35.9997 106.7638 l
35.9997 107.2638 l
153.544 107.2638 l
f*
247.7208 119.2637 m
247.7208 106.7638 l
247.2208 106.7638 l
247.2208 119.2637 l
f*
247.2208 106.7638 m
154.044 106.7638 l
154.044 107.2638 l
247.2208 107.2638 l
f*
346.3946 119.2637 m
346.3946 106.7638 l
345.8945 106.7638 l
345.8945 119.2637 l
f*
345.8945 106.7638 m
247.7208 106.7638 l
247.7208 107.2638 l
345.8945 107.2638 l
f*
575.9994 106.7638 m
346.3946 106.7638 l
346.3946 107.2638 l
575.9994 107.2638 l
f*
154.044 106.7638 m
154.044 94.2639 l
153.544 94.2639 l
153.544 106.7638 l
f*
153.544 94.2639 m
35.9997 94.2639 l
35.9997 94.7639 l
153.544 94.7639 l
f*
247.7208 106.7638 m
247.7208 94.2639 l
247.2208 94.2639 l
247.2208 106.7638 l
f*
247.2208 94.2639 m
154.044 94.2639 l
154.044 94.7639 l
247.2208 94.7639 l
f*
346.3946 106.7638 m
346.3946 94.2639 l
345.8945 94.2639 l
345.8945 106.7638 l
f*
345.8945 94.2639 m
247.7208 94.2639 l
247.7208 94.7639 l
345.8945 94.7639 l
f*
575.9994 94.2639 m
346.3946 94.2639 l
346.3946 94.7639 l
575.9994 94.7639 l
f*
0.83 0.64 0.02 0 k
106.1858 196.2142 m
113.7827 196.2142 l
113.7827 196.1575 l
106.1858 196.1575 l
f*
109.8709 183.685 m
117.5244 183.685 l
h
f*
109.5874 171.2126 m
117.2409 171.2126 l
h
f*
112.5354 158.6835 m
120.189 158.6835 l
h
f*
106.526 146.211 m
114.1795 146.211 l
h
f*
114.463 133.6819 m
122.1165 133.6819 l
h
f*
112.5354 121.2094 m
120.189 121.2094 l
h
f*
112.9323 108.6803 m
120.5858 108.6803 l
h
f*
108.5102 96.2079 m
116.1638 96.2079 l
h
f*
36 81.1843 m
184.5354 81.1843 l
h
f*
0 g
7.9999 0 0 7.9999 36 226.6015 cm
BT
/F12 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Table)Tj
2.5512 0 Td
(1.)Tj
0.9567 0 Td
(Dosing)Tj
3.196 0 Td
(strategi)Tj
3.1111 0 Td
(es)Tj
1.0346 0 Td
(for)Tj
1.4599 0 Td
(orally)Tj
2.6079 0 Td
(administra)Tj
4.5496 0 Td
(ted)Tj
1.5378 0 Td
(drugs)Tj
2.5725 0 Td
(for)Tj
1.4599 0 Td
(GBM)Tj
2.4449 0 Td
(from)Tj
2.3031 0 Td
(publishe)Tj
3.5292 0 Td
(d)Tj
0.7653 0 Td
(clinical)Tj
3.2032 0 Td
(trials.)Tj
0 Tc
-31.3301 -1.8567 Td
(Study)Tj
12.3875 0 Td
(Treatmen)Tj
4.1315 0 Td
(t)Tj
7.5827 0 Td
(Patien)Tj
2.693 0 Td
(ts)Tj
0.9637 0 Td
(\(N\))Tj
15.8317 0 Td
(Dosing)Tj
3.2315 0 Td
(strategies)Tj
/F7 1 Tf
-48.5224 -1.8071 Td
(Rich)Tj
2.0763 0 Td
(et)Tj
0.9567 0 Td
(al.)Tj
1.141 0 Td
([)Tj
0.83 0.64 0.02 0 k
(77)Tj
0 g
(])Tj
10.3536 0 Td
(Gefiniti)Tj
3.0898 0 Td
(b)Tj
10.2544 0 Td
(53)Tj
17.4474 0 Td
(500-1000m)Tj
4.5142 0 Td
(g)Tj
0.7016 0 Td
(daily)Tj
-51.0028 -1.5661 Td
(Prados)Tj
3.0048 0 Td
(et)Tj
0.9567 0 Td
(al.)Tj
1.148 0 Td
([)Tj
0.83 0.64 0.02 0 k
(78)Tj
0 g
(])Tj
9.8859 0 Td
(Erlotini)Tj
3.0898 0 Td
(b)Tj
10.2544 0 Td
(83)Tj
17.6884 0 Td
(100-500mg)Tj
4.7338 0 Td
(daily)Tj
-50.7192 -1.5591 Td
(Brown)Tj
2.9267 0 Td
(et)Tj
0.9567 0 Td
(al.)Tj
1.141 0 Td
([)Tj
0.83 0.64 0.02 0 k
(79)Tj
0 g
(])Tj
9.9284 0 Td
(Erlotini)Tj
3.0898 0 Td
(b)Tj
10.0135 0 Td
(100)Tj
18.8222 0 Td
(150mg)Tj
2.948 0 Td
(daily)Tj
-50.2019 -1.5661 Td
(Reardon)Tj
3.6779 0 Td
(et)Tj
0.9567 0 Td
(al.)Tj
1.141 0 Td
([)Tj
0.83 0.64 0.02 0 k
(80)Tj
0 g
(])Tj
9.6024 0 Td
(Imatinib)Tj
13.2946 0 Td
(33)Tj
17.412 0 Td
(500mg)Tj
2.948 0 Td
(twice)Tj
2.3386 0 Td
(daily)Tj
-50.6201 -1.5591 Td
(Wen)Tj
2.1686 0 Td
(et)Tj
0.9638 0 Td
(al.)Tj
1.1409 0 Td
([)Tj
0.83 0.64 0.02 0 k
(81)Tj
0 g
(])Tj
10.3536 0 Td
(Imatinib)Tj
13.2946 0 Td
(55)Tj
17.6884 0 Td
(600-800mg)Tj
4.7338 0 Td
(daily)Tj
-51.3358 -1.5662 Td
(Raymond)Tj
4.1528 0 Td
(et)Tj
0.9567 0 Td
(al.)Tj
1.148 0 Td
([)Tj
0.83 0.64 0.02 0 k
(82)Tj
0 g
(])Tj
9.3615 0 Td
(Imatinib)Tj
13.0537 0 Td
(112)Tj
14.7473 0 Td
(600mg)Tj
2.9481 0 Td
(daily500)Tj
4.2945 0 Td
(mg)Tj
1.5236 0 Td
(twice)Tj
2.3387 0 Td
(daily)Tj
-54.2839 -1.559 Td
(Reardon)Tj
3.6779 0 Td
(et)Tj
0.9567 0 Td
(al.)Tj
1.141 0 Td
([)Tj
0.83 0.64 0.02 0 k
(15)Tj
0 g
(])Tj
9.4394 0 Td
(Lapatin)Tj
3.0473 0 Td
(ib)Tj
10.4103 0 Td
(41)Tj
17.171 0 Td
(1000mg)Tj
3.43 0 Td
(twice)Tj
2.3386 0 Td
(daily)Tj
-51.6618 -1.5662 Td
(Thiessen)Tj
3.7701 0 Td
(et)Tj
0.9567 0 Td
(al.)Tj
1.148 0 Td
([)Tj
0.83 0.64 0.02 0 k
(16)Tj
0 g
(])Tj
9.3898 0 Td
(Lapatin)Tj
3.0473 0 Td
(ib)Tj
10.4103 0 Td
(17)Tj
16.0372 0 Td
(1000-1500m)Tj
4.9961 0 Td
(g)Tj
0.7015 0 Td
(twice)Tj
2.3386 0 Td
(daily)Tj
-52.2429 -1.559 Td
(Chien)Tj
2.6717 0 Td
(et)Tj
0.9567 0 Td
(al.)Tj
1.1409 0 Td
([)Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
(])Tj
9.9426 0 Td
(Lapatin)Tj
3.0473 0 Td
(ib)Tj
10.4103 0 Td
(25)Tj
10.2615 0 Td
(1000-5250m)Tj
4.9961 0 Td
(g)Tj
0.6945 0 Td
(twice)Tj
2.3386 0 Td
(daily)Tj
2.1756 0 Td
(for)Tj
1.4032 0 Td
(two)Tj
1.722 0 Td
(days)Tj
2.0198 0 Td
(in)Tj
1.0488 0 Td
(a)Tj
0.6661 0 Td
(5-day)Tj
2.4804 0 Td
(cycle)Tj
0.83 0.64 0.02 0 k
/F10 1 Tf
-0.025 Tc
-61.9304 -1.878 Td
(https://do)Tj
3.5575 0 Td
(i.org/10.1371/j)Tj
5.4425 0 Td
(ournal.pc)Tj
3.4583 0 Td
(bi.1005924.)Tj
4.4292 0 Td
(t001)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 169.285 23.6976 re
W* n
q
169.2283 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 338.0598 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Mathematic)Tj
5.0882 0 Td
(al)Tj
0.9779 0 Td
(modeling)Tj
4.2024 0 Td
(identifies)Tj
4.082 0 Td
(optimum)Tj
3.9968 0 Td
(lapatinib)Tj
3.8623 0 Td
(dosing)Tj
3.111 0 Td
(schedules)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
142.5827 34.9228 m
295.8236 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(Computationa)Tj
6.1229 0 Td
(l)Tj
0.4322 0 Td
(Biology)Tj
3.4371 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https:/)Tj
2.6788 0 Td
(/doi.org/10.13)Tj
6.0094 0 Td
(71/journal.p)Tj
5.1166 0 Td
(cbi.1005924)Tj
0 g
6.3497 0 Td
(January)Tj
3.7134 0 Td
(2,)Tj
1.0417 0 Td
(2018)Tj
26.9081 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
0.496 0 Td
(24)Tj
/F9 1 Tf
-0.025 Tc
-66.402 84.0904 Td
(Competing)Tj
4.3795 0 Td
(interests)Tj
3.3307 0 Td
(:)Tj
/F10 1 Tf
0.4819 0 Td
(The)Tj
1.5875 0 Td
(authors)Tj
3.0401 0 Td
(have)Tj
1.963 0 Td
(declared)Tj
-14.7827 -1.3748 Td
(that)Tj
1.6228 0 Td
(no)Tj
1.1693 0 Td
(competing)Tj
4.1599 0 Td
(interests)Tj
ET
endstream
endobj
42 0 obj
<>stream
endstream
endobj
43 0 obj
<>stream
endstream
endobj
44 0 obj
<>stream
endstream
endobj
45 0 obj
<>stream
endstream
endobj
46 0 obj
<>stream
endstream
endobj
47 0 obj
<>stream
endstream
endobj
48 0 obj
<>stream
endstream
endobj
49 0 obj
<>stream
endstream
endobj
50 0 obj
<>stream
endstream
endobj
51 0 obj
<>stream
endstream
endobj
52 0 obj
<>stream
endstream
endobj
53 0 obj
<>stream
endstream
endobj
54 0 obj
<>stream
endstream
endobj
55 0 obj
<>stream
endstream
endobj
56 0 obj
<>stream
endstream
endobj
57 0 obj
<>stream
endstream
endobj
58 0 obj
<>stream
endstream
endobj
59 0 obj
<>stream
endstream
endobj
60 0 obj
<>stream
BT
10.3394 82.7156 Td
(exist.)Tj
ET
Q
endstream
endobj
61 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 62 0 R/Contents 63 0 R/TrimBox[0 0 612 792]>>
endobj
62 0 obj
[64 0 R 65 0 R 66 0 R 67 0 R 68 0 R 69 0 R 70 0 R 71 0 R 72 0 R 73 0 R 74 0 R 75 0 R 76 0 R]
endobj
64 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref017)>>
endobj
65 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref018)>>
endobj
66 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref019)>>
endobj
67 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref020)>>
endobj
68 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref021)>>
endobj
69 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref022)>>
endobj
70 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref023)>>
endobj
71 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref027)>>
endobj
72 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref028)>>
endobj
73 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref029)>>
endobj
74 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref030)>>
endobj
75 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.ref031)>>
endobj
76 0 obj
<>/Border[0 0 0]/A 77 0 R>>
endobj
77 0 obj
<>
endobj
63 0 obj
[78 0 R 79 0 R 80 0 R 81 0 R 82 0 R 83 0 R 84 0 R 85 0 R 86 0 R 87 0 R 88 0 R 89 0 R 90 0 R]
endobj
78 0 obj
<>stream
q
0.83 0.64 0.02 0 k
240.8882 706.337 m
250.4126 706.337 l
h
f*
409.8898 550.3181 m
419.4142 550.3181 l
h
f*
502.6961 524.2961 m
512.2205 524.2961 l
h
f*
379.2189 459.326 m
388.7433 459.326 l
h
f*
287.7165 394.2992 m
297.2409 394.2992 l
h
f*
429.052 290.3244 m
438.5764 290.3244 l
h
f*
203.4142 251.3197 m
212.9386 251.3197 l
h
f*
218.0976 251.3197 m
227.622 251.3197 l
h
f*
404.1071 173.3102 m
413.5748 173.3102 l
h
f*
362.0409 147.3449 m
371.5654 147.3449 l
h
f*
440.9575 147.3449 m
450.4819 147.3449 l
h
f*
304.8378 134.3055 m
314.3622 134.3055 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 200.0125 707.4141 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(tolerated)Tj
3.7473 0 Td
([)Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
(].)Tj
2.0806 0 Td
(However,)Tj
4.0762 0 Td
(the)Tj
1.4684 0 Td
(question)Tj
3.6623 0 Td
(remains)Tj
3.4413 0 Td
(whether)Tj
3.4752 0 Td
(an)Tj
1.2076 0 Td
(altered)Tj
2.9423 0 Td
(dosing)Tj
2.897 0 Td
(strategy)Tj
3.3278 0 Td
(might)Tj
-32.326 -1.3039 Td
(increase)Tj
3.4695 0 Td
(the)Tj
1.4684 0 Td
(efficacy)Tj
3.2258 0 Td
(of)Tj
1.0148 0 Td
(this)Tj
1.6724 0 Td
(agent.)Tj
2.6135 0 Td
(Due)Tj
1.9106 0 Td
(to)Tj
1.0261 0 Td
(ethical)Tj
2.8403 0 Td
(concerns)Tj
3.8268 0 Td
(of)Tj
1.0147 0 Td
(testing)Tj
2.88 0 Td
(several)Tj
2.9367 0 Td
(dosing)Tj
2.897 0 Td
(strategies)Tj
3.9231 0 Td
(in)Tj
-36.7197 -1.2982 Td
(the)Tj
1.4683 0 Td
(absence)Tj
3.3392 0 Td
(of)Tj
1.0148 0 Td
(preclinical)Tj
4.388 0 Td
(data)Tj
1.9162 0 Td
(suggesting)Tj
4.405 0 Td
(their)Tj
2.1033 0 Td
(benefit,)Tj
3.2031 0 Td
(as)Tj
1.0148 0 Td
(well)Tj
1.8199 0 Td
(as)Tj
1.0147 0 Td
(to)Tj
1.0262 0 Td
(speed)Tj
2.4718 0 Td
(up)Tj
1.2642 0 Td
(discovery,)Tj
4.2406 0 Td
(mathe-)Tj
-34.6901 -1.2983 Td
(matical)Tj
3.1407 0 Td
(modeling)Tj
4.0252 0 Td
(of)Tj
1.0148 0 Td
(treatment)Tj
4.1385 0 Td
(response)Tj
3.7304 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
1.1508 0 Td
(used)Tj
2.058 0 Td
(to)Tj
1.0261 0 Td
(identify)Tj
3.2939 0 Td
(predicted)Tj
4.0025 0 Td
(best)Tj
1.8084 0 Td
(administration)Tj
-31.0164 -1.2983 Td
(schedules.)Tj
4.2632 0 Td
(Here,)Tj
2.4321 0 Td
(we)Tj
1.3323 0 Td
(explored)Tj
3.6964 0 Td
(continuous)Tj
4.7395 0 Td
(and)Tj
1.7291 0 Td
(pulsatile)Tj
3.5433 0 Td
(dosing)Tj
2.897 0 Td
(strategies)Tj
3.9231 0 Td
(in)Tj
1.0318 0 Td
(an)Tj
1.2019 0 Td
(EGFR-mutant)Tj
-30.7897 -1.3039 Td
(GBM)Tj
2.4094 0 Td
(cell)Tj
1.559 0 Td
(line,)Tj
1.9276 0 Td
(and)Tj
1.7291 0 Td
(used)Tj
2.0636 0 Td
(mathematical)Tj
5.6466 0 Td
(and)Tj
1.7291 0 Td
(statistical)Tj
3.9061 0 Td
(modeling)Tj
4.0252 0 Td
(to)Tj
1.0261 0 Td
(determine)Tj
4.3257 0 Td
(optimal)Tj
3.3052 0 Td
(lapatinib)Tj
-33.6527 -1.2982 Td
(dosing)Tj
2.8969 0 Td
(schedules)Tj
4.0422 0 Td
(for)Tj
1.3833 0 Td
(inhibiting)Tj
4.1839 0 Td
(tumor)Tj
2.7439 0 Td
(growth.)Tj
-14.054 -1.2983 Td
(The)Tj
1.7858 0 Td
(use)Tj
1.5307 0 Td
(of)Tj
1.0148 0 Td
(mathematical)Tj
5.6466 0 Td
(models)Tj
3.1067 0 Td
(for)Tj
1.3833 0 Td
(treatment)Tj
4.1386 0 Td
(optimization)Tj
5.3631 0 Td
(is)Tj
0.8447 0 Td
(part)Tj
1.8425 0 Td
(of)Tj
1.0148 0 Td
(a)Tj
0.6576 0 Td
(growing)Tj
3.5263 0 Td
(effort)Tj
2.3981 0 Td
(to)Tj
-35.4498 -1.3039 Td
(improve)Tj
3.5773 0 Td
(clinical)Tj
3.0784 0 Td
(trial)Tj
1.8368 0 Td
(design)Tj
2.8119 0 Td
(for)Tj
1.389 0 Td
(cancer)Tj
2.8403 0 Td
(patients.)Tj
3.5943 0 Td
(Many)Tj
2.5512 0 Td
(models)Tj
3.1067 0 Td
(have)Tj
2.058 0 Td
(been)Tj
2.1203 0 Td
(developed)Tj
4.2746 0 Td
(to)Tj
1.0261 0 Td
(investi-)Tj
-34.2649 -1.2983 Td
(gate)Tj
1.8425 0 Td
(the)Tj
1.4683 0 Td
(relationship)Tj
4.9889 0 Td
(between)Tj
3.5263 0 Td
(toxicity)Tj
3.2031 0 Td
(and)Tj
1.7292 0 Td
(dose)Tj
2.0409 0 Td
(in)Tj
1.0318 0 Td
(an)Tj
1.2019 0 Td
(attempt)Tj
3.3108 0 Td
(to)Tj
1.0262 0 Td
(better)Tj
2.5398 0 Td
(characterize)Tj
5.0343 0 Td
(the)Tj
1.4683 0 Td
(toxicity)Tj
-34.4123 -1.2983 Td
(profile)Tj
2.8402 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(therapeutic)Tj
4.7338 0 Td
(products)Tj
3.7531 0 Td
(under)Tj
2.6192 0 Td
(investigation.)Tj
5.5842 0 Td
(For)Tj
1.627 0 Td
(instance,)Tj
3.7474 0 Td
(Huitema)Tj
3.7587 0 Td
(et)Tj
0.9411 0 Td
(al.)Tj
1.1282 0 Td
(reviewed)Tj
-33.2161 -1.3039 Td
(several)Tj
2.931 0 Td
(differential)Tj
4.6034 0 Td
(equation-based)Tj
6.3382 0 Td
(models)Tj
3.1068 0 Td
(of)Tj
1.0148 0 Td
(chemotherapy-induced)Tj
9.5413 0 Td
(myelosuppression,)Tj
7.6592 0 Td
(car-)Tj
-35.1947 -1.2982 Td
(diovascular)Tj
4.7735 0 Td
(events)Tj
2.7269 0 Td
(and)Tj
1.7348 0 Td
(other)Tj
2.347 0 Td
(ordinal)Tj
3.1181 0 Td
(adverse)Tj
3.2202 0 Td
(events)Tj
2.7269 0 Td
([)Tj
0.83 0.64 0.02 0 k
(18)Tj
0 g
(].)Tj
2.0749 0 Td
(Amantea)Tj
3.8665 0 Td
(et)Tj
0.9411 0 Td
(al.)Tj
1.1225 0 Td
(developed)Tj
4.2746 0 Td
(a)Tj
0.652 0 Td
(model)Tj
-33.579 -1.2983 Td
(incorporating)Tj
5.7429 0 Td
(exposure,)Tj
4.0422 0 Td
(biomarkers,)Tj
5.0059 0 Td
(efficacy)Tj
3.2202 0 Td
(endpoints)Tj
4.2179 0 Td
(and)Tj
1.7348 0 Td
(adverse)Tj
3.2145 0 Td
(events)Tj
2.7269 0 Td
(in)Tj
1.0374 0 Td
(models)Tj
3.1068 0 Td
(describ-)Tj
-34.0495 -1.3039 Td
(ing)Tj
1.5023 0 Td
(the)Tj
1.4683 0 Td
(treatment)Tj
4.1329 0 Td
(response)Tj
3.7361 0 Td
(of)Tj
1.0148 0 Td
(patients)Tj
3.3675 0 Td
(with)Tj
1.9956 0 Td
(gastrointestinal)Tj
6.3495 0 Td
(stromal)Tj
3.2599 0 Td
(tumors)Tj
3.1011 0 Td
([)Tj
0.83 0.64 0.02 0 k
(19)Tj
0 g
(].)Tj
2.0806 0 Td
(Their)Tj
2.4207 0 Td
(analysis)Tj
-34.4293 -1.2983 Td
(uncovered)Tj
4.4276 0 Td
(a)Tj
0.652 0 Td
(correlation)Tj
4.6204 0 Td
(between)Tj
3.5263 0 Td
(adverse)Tj
3.2145 0 Td
(events)Tj
2.7326 0 Td
(and)Tj
1.7291 0 Td
(efficacy:)Tj
3.4469 0 Td
(drug-induced)Tj
5.7089 0 Td
(increases)Tj
3.8325 0 Td
(in)Tj
1.0374 0 Td
(dia-)Tj
-34.9282 -1.2982 Td
(stolic)Tj
2.3243 0 Td
(blood)Tj
2.5115 0 Td
(pressure)Tj
3.5773 0 Td
(were)Tj
2.1203 0 Td
(positively)Tj
4.0195 0 Td
(associated)Tj
4.2576 0 Td
(with)Tj
1.9956 0 Td
(overall)Tj
2.9027 0 Td
(survival.)Tj
3.5603 0 Td
(Another)Tj
3.5829 0 Td
(study)Tj
2.3925 0 Td
(by)Tj
1.1792 0 Td
(Hui-)Tj
-34.4237 -1.2983 Td
(tema)Tj
2.194 0 Td
(et)Tj
0.941 0 Td
(al.)Tj
1.1282 0 Td
(examined)Tj
4.1272 0 Td
(the)Tj
1.4684 0 Td
(effects)Tj
2.7269 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(anti-angiogenic)Tj
6.4687 0 Td
(drug)Tj
2.1146 0 Td
(E7080)Tj
2.6929 0 Td
(and)Tj
1.7291 0 Td
(its)Tj
1.1452 0 Td
(drug-induced)Tj
-29.2193 -1.3039 Td
(adverse)Tj
3.2144 0 Td
(events)Tj
2.7269 0 Td
(in)Tj
1.0375 0 Td
(an)Tj
1.2019 0 Td
(attempt)Tj
3.3108 0 Td
(to)Tj
1.0262 0 Td
(evaluate)Tj
3.4639 0 Td
(dosing)Tj
2.8913 0 Td
(regimens)Tj
3.9004 0 Td
(with)Tj
2.0013 0 Td
(regard)Tj
2.8119 0 Td
(to)Tj
1.0262 0 Td
(their)Tj
2.1089 0 Td
(reduction)Tj
4.1103 0 Td
(of)Tj
-34.8319 -1.2983 Td
(adverse)Tj
3.2144 0 Td
(events)Tj
2.7269 0 Td
(and)Tj
1.7348 0 Td
(improvement)Tj
5.6693 0 Td
(of)Tj
1.0148 0 Td
(efficacy)Tj
3.2201 0 Td
([)Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
(].)Tj
2.0806 0 Td
(They)Tj
2.2337 0 Td
(found)Tj
2.6192 0 Td
(that)Tj
1.7802 0 Td
(proteinuria)Tj
4.7508 0 Td
(could)Tj
2.4548 0 Td
(be)Tj
1.1508 0 Td
(best)Tj
-34.6504 -1.2983 Td
(described)Tj
4.0535 0 Td
(by)Tj
1.1792 0 Td
(a)Tj
0.6519 0 Td
(discrete-time)Tj
5.4765 0 Td
(Markov)Tj
3.3789 0 Td
(transition)Tj
4.1216 0 Td
(model.)Tj
2.965 0 Td
(Similarly,)Tj
4.0308 0 Td
(Fuhr)Tj
2.1713 0 Td
(et)Tj
0.9411 0 Td
(al.)Tj
1.1282 0 Td
(constructed)Tj
4.9323 0 Td
(a)Tj
0.6519 0 Td
(con-)Tj
-35.6822 -1.3039 Td
(tinuous-time)Tj
5.4141 0 Td
(Markov)Tj
3.3789 0 Td
(model)Tj
2.7439 0 Td
(to)Tj
1.0261 0 Td
(investigate)Tj
4.4617 0 Td
(erlotinib-induced)Tj
7.251 0 Td
(adverse)Tj
3.2145 0 Td
(events)Tj
2.7269 0 Td
(in)Tj
1.0375 0 Td
(non-small)Tj
4.2802 0 Td
(cell)Tj
-35.5348 -1.2982 Td
(lung)Tj
2.0069 0 Td
(cancer)Tj
2.8459 0 Td
(patients;)Tj
3.5943 0 Td
(their)Tj
2.1033 0 Td
(simulation)Tj
4.4958 0 Td
(results)Tj
2.8119 0 Td
(provided)Tj
3.8154 0 Td
(support)Tj
3.3222 0 Td
(for)Tj
1.3833 0 Td
(the)Tj
1.474 0 Td
(use)Tj
1.5307 0 Td
(of)Tj
1.0148 0 Td
(high-dose)Tj
4.1782 0 Td
(pulses)Tj
-34.5767 -1.2983 Td
(as)Tj
1.0147 0 Td
(an)Tj
1.2019 0 Td
(alternative)Tj
4.4164 0 Td
(dosing)Tj
2.897 0 Td
(strategy)Tj
3.3278 0 Td
(for)Tj
1.389 0 Td
(addressing)Tj
4.507 0 Td
(acquired)Tj
3.7021 0 Td
(resistance)Tj
4.1272 0 Td
(often)Tj
2.2847 0 Td
(found)Tj
2.6192 0 Td
(when)Tj
2.4038 0 Td
(using)Tj
2.3924 0 Td
(a)Tj
-36.2832 -1.3039 Td
(low)Tj
1.6554 0 Td
(continuous)Tj
4.7395 0 Td
(dose)Tj
2.0352 0 Td
([)Tj
0.83 0.64 0.02 0 k
(21)Tj
0 g
(].)Tj
2.0806 0 Td
(In)Tj
1.1056 0 Td
(these)Tj
2.2563 0 Td
(examples,)Tj
4.1329 0 Td
(a)Tj
0.6576 0 Td
(delicate)Tj
3.2599 0 Td
(balance)Tj
3.2371 0 Td
(between)Tj
3.532 0 Td
(toxicity)Tj
3.1974 0 Td
(and)Tj
1.7291 0 Td
(efficacy)Tj
-33.6186 -1.2983 Td
(determines)Tj
4.6828 0 Td
(the)Tj
1.4683 0 Td
(most)Tj
2.2053 0 Td
(efficacious)Tj
4.4334 0 Td
(dose.)Tj
-11.5936 -1.2983 Td
(In)Tj
1.1111 0 Td
(addition)Tj
3.6 0 Td
(to)Tj
1.0205 0 Td
(understanding)Tj
6.0718 0 Td
(toxicity)Tj
3.2031 0 Td
(profiles,)Tj
3.4242 0 Td
(mathematical)Tj
5.6466 0 Td
(models)Tj
3.1067 0 Td
(have)Tj
2.058 0 Td
(also)Tj
1.7688 0 Td
(been)Tj
2.1203 0 Td
(used)Tj
2.0636 0 Td
(to)Tj
-36.3909 -1.2982 Td
(model)Tj
2.7439 0 Td
(pre-clinical)Tj
4.7395 0 Td
(data)Tj
1.9105 0 Td
(from)Tj
2.2053 0 Td
(animal)Tj
2.9707 0 Td
(or)Tj
1.0999 0 Td
(in)Tj
1.0374 0 Td
(vitro)Tj
2.1147 0 Td
(systems)Tj
3.2995 0 Td
(in)Tj
1.0375 0 Td
(order)Tj
2.4207 0 Td
(to)Tj
1.0262 0 Td
(bypass)Tj
2.8516 0 Td
(the)Tj
1.474 0 Td
(difficulty)Tj
3.8041 0 Td
(associ-)Tj
-34.7355 -1.3039 Td
(ated)Tj
1.9048 0 Td
(with)Tj
1.9956 0 Td
(directly)Tj
3.2315 0 Td
(observing)Tj
4.1272 0 Td
(tumor)Tj
2.7439 0 Td
(progression)Tj
4.9209 0 Td
(in)Tj
1.0318 0 Td
(humans.)Tj
3.668 0 Td
(Translational)Tj
5.5276 0 Td
(models)Tj
3.101 0 Td
(incorporat-)Tj
-32.2523 -1.2983 Td
(ing)Tj
1.5023 0 Td
(in)Tj
1.0318 0 Td
(vitro)Tj
2.1203 0 Td
(or)Tj
1.0998 0 Td
(animal)Tj
2.9651 0 Td
(data)Tj
1.9162 0 Td
(have)Tj
2.0579 0 Td
(also)Tj
1.7688 0 Td
(be)Tj
1.1509 0 Td
(developed)Tj
4.2746 0 Td
(to)Tj
1.0205 0 Td
(investigate)Tj
4.4617 0 Td
(the)Tj
1.474 0 Td
(relationship)Tj
4.9889 0 Td
(between)Tj
-31.8328 -1.2983 Td
(efficacy)Tj
3.2201 0 Td
(endpoints)Tj
4.2179 0 Td
(and)Tj
1.7348 0 Td
(exposure.)Tj
4.0365 0 Td
(Mould)Tj
2.9254 0 Td
(et)Tj
0.941 0 Td
(al.)Tj
1.1226 0 Td
(provided)Tj
3.821 0 Td
(a)Tj
0.652 0 Td
(comprehensive)Tj
6.2872 0 Td
(review)Tj
2.846 0 Td
(of)Tj
1.0148 0 Td
(how)Tj
1.9389 0 Td
(the)Tj
1.4683 0 Td
(use)Tj
-36.2265 -1.3039 Td
(of)Tj
1.0147 0 Td
(mathematical)Tj
5.6466 0 Td
(models)Tj
3.1011 0 Td
(can)Tj
1.6271 0 Td
(aid)Tj
1.4513 0 Td
(early)Tj
2.1487 0 Td
(development)Tj
5.4084 0 Td
(of)Tj
1.0148 0 Td
(anti-cancer)Tj
4.7452 0 Td
(therapy,)Tj
3.4696 0 Td
(in)Tj
1.0375 0 Td
(particular)Tj
4.1102 0 Td
(for)Tj
-34.7752 -1.2982 Td
(describing)Tj
4.3823 0 Td
(tumor)Tj
2.7439 0 Td
(volume)Tj
3.1975 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.6519 0 Td
(function)Tj
3.6283 0 Td
(of)Tj
1.0148 0 Td
(drug)Tj
2.1147 0 Td
(exposure)Tj
3.8154 0 Td
([)Tj
0.83 0.64 0.02 0 k
(22)Tj
0 g
(].)Tj
2.0749 0 Td
(Most)Tj
2.2791 0 Td
(papers)Tj
2.8459 0 Td
(these)Tj
2.2564 0 Td
(authors)Tj
3.2428 0 Td
(dis-)Tj
-35.2627 -1.2983 Td
(cussed)Tj
2.8402 0 Td
(describe)Tj
3.5263 0 Td
(changing)Tj
3.9005 0 Td
(tumor)Tj
2.7439 0 Td
(volumes)Tj
3.5603 0 Td
(using)Tj
2.3867 0 Td
(differential)Tj
4.6035 0 Td
(equation)Tj
3.736 0 Td
(models)Tj
3.1068 0 Td
(with)Tj
1.9955 0 Td
(two)Tj
1.7065 0 Td
(terms:)Tj
-34.1062 -1.3039 Td
(net)Tj
1.4796 0 Td
(tumor)Tj
2.7326 0 Td
(growth)Tj
3.0671 0 Td
(in)Tj
1.0261 0 Td
(the)Tj
1.457 0 Td
(absence)Tj
3.3335 0 Td
(of)Tj
1.0035 0 Td
(therapeutic)Tj
4.7225 0 Td
(candidates)Tj
4.456 0 Td
(and)Tj
1.7235 0 Td
(a)Tj
0.6463 0 Td
(drug-induced)Tj
5.6976 0 Td
(shrinkage)Tj
4.1045 0 Td
(effect)Tj
-35.4498 -1.2983 Td
([)Tj
0.83 0.64 0.02 0 k
(23)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(27)Tj
0 g
(].)Tj
3.5432 0 Td
(These)Tj
2.5682 0 Td
(models)Tj
3.1068 0 Td
(suggest)Tj
3.1181 0 Td
(that)Tj
1.7801 0 Td
(the)Tj
1.4683 0 Td
(best)Tj
1.8085 0 Td
(strategy)Tj
3.3279 0 Td
(for)Tj
1.3889 0 Td
(inhibiting)Tj
4.184 0 Td
(tumor)Tj
2.7439 0 Td
(growth)Tj
3.0727 0 Td
(is)Tj
0.8447 0 Td
(to)Tj
1.0262 0 Td
(maxi-)Tj
-33.9815 -1.2983 Td
(mize)Tj
2.1429 0 Td
(the)Tj
1.4684 0 Td
(effect)Tj
2.364 0 Td
(of)Tj
1.0148 0 Td
(drug)Tj
2.1147 0 Td
(exposure,)Tj
4.0422 0 Td
(which)Tj
2.6475 0 Td
(often)Tj
2.2847 0 Td
(corresponds)Tj
5.142 0 Td
(to)Tj
1.0262 0 Td
(higher)Tj
2.8006 0 Td
(drug)Tj
2.1089 0 Td
(concentrations.)Tj
-29.1569 -1.3039 Td
(However,)Tj
4.0761 0 Td
(given)Tj
2.3811 0 Td
(toxicity)Tj
3.1975 0 Td
(constraints,)Tj
4.8642 0 Td
(high)Tj
2.0069 0 Td
(drug)Tj
2.1147 0 Td
(concentrations)Tj
6.1795 0 Td
(usually)Tj
3.016 0 Td
(cannot)Tj
2.982 0 Td
(be)Tj
1.1509 0 Td
(achieved)Tj
3.702 0 Td
(for)Tj
-35.6709 -1.2982 Td
(long)Tj
1.9842 0 Td
(time)Tj
2.0296 0 Td
(periods.)Tj
3.4185 0 Td
(An)Tj
1.457 0 Td
(alternative)Tj
4.4164 0 Td
(strategy)Tj
3.3278 0 Td
(is)Tj
0.8504 0 Td
(to)Tj
1.0205 0 Td
(administer)Tj
4.5411 0 Td
(drugs)Tj
2.4718 0 Td
(in)Tj
1.0374 0 Td
(pulsatile)Tj
3.5377 0 Td
(doses)Tj
2.4037 0 Td
(in)Tj
1.0318 0 Td
(order)Tj
2.4208 0 Td
(to)Tj
-35.9487 -1.2983 Td
(circumvent)Tj
4.7791 0 Td
(the)Tj
1.4684 0 Td
(toxicity)Tj
3.1974 0 Td
(limit.)Tj
2.3471 0 Td
(A)Tj
0.9014 0 Td
(small)Tj
2.3301 0 Td
(trial)Tj
1.8368 0 Td
(using)Tj
2.3868 0 Td
(weekly)Tj
2.948 0 Td
(pulsatile)Tj
3.5433 0 Td
(high-dose)Tj
4.1782 0 Td
(erlotinib)Tj
3.6567 0 Td
(showed)Tj
-33.5733 -1.2983 Td
(promising)Tj
4.3426 0 Td
(results)Tj
2.812 0 Td
(for)Tj
1.3832 0 Td
(controlling)Tj
4.6488 0 Td
(central)Tj
2.9651 0 Td
(nervous)Tj
3.4129 0 Td
(system)Tj
2.9423 0 Td
(metastases)Tj
4.4334 0 Td
(from)Tj
2.2053 0 Td
(epidermal)Tj
4.2519 0 Td
(growth)Tj
-33.3975 -1.3039 Td
(factor)Tj
2.5398 0 Td
(receptor-mutant)Tj
6.8314 0 Td
(non-small)Tj
4.286 0 Td
(cell)Tj
1.559 0 Td
(lung)Tj
2.0069 0 Td
(cancer)Tj
2.846 0 Td
([)Tj
0.83 0.64 0.02 0 k
(28)Tj
0 g
(].)Tj
2.075 0 Td
(Crooke)Tj
3.1861 0 Td
(et)Tj
0.9411 0 Td
(al.)Tj
1.1282 0 Td
(also)Tj
1.7688 0 Td
(performed)Tj
4.4673 0 Td
(computa-)Tj
-33.6356 -1.2983 Td
(tional)Tj
2.5171 0 Td
(analyses)Tj
3.4866 0 Td
(comparing)Tj
4.5751 0 Td
(continuous)Tj
4.7338 0 Td
(and)Tj
1.7291 0 Td
(pulsatile)Tj
3.5433 0 Td
(dosing)Tj
2.897 0 Td
(and)Tj
1.7291 0 Td
(found)Tj
2.6192 0 Td
(that)Tj
1.7802 0 Td
(pulsed)Tj
2.8233 0 Td
(therapy)Tj
3.2428 0 Td
(is)Tj
-35.6766 -1.2982 Td
(more)Tj
2.3414 0 Td
(effective)Tj
3.5092 0 Td
(than)Tj
2.0296 0 Td
(continuous)Tj
4.7338 0 Td
(therapy)Tj
3.2485 0 Td
([)Tj
0.83 0.64 0.02 0 k
(29)Tj
0 g
(].)Tj
2.075 0 Td
(A)Tj
0.9071 0 Td
(clinical)Tj
3.0727 0 Td
(trial)Tj
1.8368 0 Td
([)Tj
0.83 0.64 0.02 0 k
(30)Tj
0 g
(])Tj
1.8539 0 Td
(based)Tj
2.4718 0 Td
(on)Tj
1.2756 0 Td
(mathematical)Tj
-29.3554 -1.3039 Td
(modeling)Tj
4.0251 0 Td
(and)Tj
1.7291 0 Td
(preclinical)Tj
4.388 0 Td
([)Tj
0.83 0.64 0.02 0 k
(31)Tj
0 g
(])Tj
1.8539 0 Td
(experiments)Tj
5.1363 0 Td
(demonstrated)Tj
5.76 0 Td
(that)Tj
1.7802 0 Td
(a)Tj
0.6519 0 Td
(combined)Tj
4.2463 0 Td
(low-dose)Tj
3.8267 0 Td
(continu-)Tj
-33.3975 -1.2983 Td
(ous)Tj
1.6157 0 Td
(and)Tj
1.7291 0 Td
(high-dose)Tj
4.1783 0 Td
(pulsed)Tj
2.8232 0 Td
(erlotinib)Tj
3.6567 0 Td
(schedule)Tj
3.6794 0 Td
(was)Tj
1.7007 0 Td
(successful)Tj
4.1613 0 Td
(at)Tj
0.9524 0 Td
(preventing)Tj
4.5354 0 Td
(progression)Tj
4.9209 0 Td
(in)Tj
-33.9531 -1.2983 Td
(patients)Tj
3.3675 0 Td
(with)Tj
1.9956 0 Td
(CNS)Tj
2.0976 0 Td
(metastases)Tj
4.4333 0 Td
(but)Tj
1.5534 0 Td
(did)Tj
1.5421 0 Td
(not)Tj
1.576 0 Td
(show)Tj
2.2961 0 Td
(significantly)Tj
5.091 0 Td
(delayed)Tj
3.2541 0 Td
(emergence)Tj
4.5468 0 Td
(of)Tj
1.0147 0 Td
(resistance)Tj
-32.7682 -1.3039 Td
(due)Tj
1.6951 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.474 0 Td
(T790M)Tj
3.1464 0 Td
(EGFR)Tj
2.6532 0 Td
(mutation.)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 169.285 23.6976 re
W* n
q
169.2283 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 338.0598 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Mathematic)Tj
5.0882 0 Td
(al)Tj
0.9779 0 Td
(modeling)Tj
4.2024 0 Td
(identifies)Tj
4.082 0 Td
(optimum)Tj
3.9968 0 Td
(lapatinib)Tj
3.8623 0 Td
(dosing)Tj
3.111 0 Td
(schedules)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
142.5827 34.9228 m
295.8236 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(Computationa)Tj
6.1229 0 Td
(l)Tj
0.4322 0 Td
(Biology)Tj
3.4371 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https:/)Tj
2.6788 0 Td
(/doi.org/10.13)Tj
6.0094 0 Td
(71/journal.p)Tj
5.1166 0 Td
(cbi.1005924)Tj
0 g
6.3497 0 Td
(January)Tj
3.7134 0 Td
(2,)Tj
1.0417 0 Td
(2018)Tj
26.9081 0 Td
(3)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
79 0 obj
<>stream
endstream
endobj
80 0 obj
<>stream
endstream
endobj
81 0 obj
<>stream
endstream
endobj
82 0 obj
<>stream
endstream
endobj
83 0 obj
<>stream
endstream
endobj
84 0 obj
<>stream
endstream
endobj
85 0 obj
<>stream
endstream
endobj
86 0 obj
<>stream
endstream
endobj
87 0 obj
<>stream
endstream
endobj
88 0 obj
<>stream
endstream
endobj
89 0 obj
<>stream
endstream
endobj
90 0 obj
<>stream
BT
66.402 0 Td
(24)Tj
ET
Q
endstream
endobj
91 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 98 0 R/Contents 99 0 R/TrimBox[0 0 612 792]>>
endobj
98 0 obj
[100 0 R 101 0 R]
endobj
100 0 obj
<>/Border[0 0 0]/Dest(Rpcbi.1005924.g001)>>
endobj
101 0 obj
<>/Border[0 0 0]/A 102 0 R>>
endobj
102 0 obj
<>
endobj
99 0 obj
[103 0 R 104 0 R 105 0 R 106 0 R 107 0 R 108 0 R 109 0 R 110 0 R 111 0 R 112 0 R]
endobj
103 0 obj
<>stream
q
0.83 0.64 0.02 0 k
397.2472 680.315 m
416.8063 680.315 l
h
f*
0 g
1 j
1 J
0 w
10 0 0 10 211.9748 707.4141 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Here)Tj
2.211 0 Td
(we)Tj
1.3266 0 Td
(present)Tj
3.1634 0 Td
(a)Tj
0.652 0 Td
(computational)Tj
6.0491 0 Td
(modeling)Tj
4.0251 0 Td
(approach)Tj
3.9515 0 Td
(incorporating)Tj
5.7486 0 Td
(both)Tj
2.058 0 Td
(toxicity)Tj
3.2031 0 Td
(data)Tj
1.9105 0 Td
(from)Tj
-35.4951 -1.3039 Td
(phase)Tj
2.4831 0 Td
(I)Tj
0.5612 0 Td
(clinical)Tj
3.0728 0 Td
(trials)Tj
2.1996 0 Td
(and)Tj
1.7292 0 Td
(efficacy)Tj
3.2201 0 Td
(data)Tj
1.9162 0 Td
(from)Tj
2.2053 0 Td
(pre-clinical)Tj
4.7395 0 Td
(research)Tj
3.5547 0 Td
(to)Tj
1.0261 0 Td
(examine)Tj
3.6 0 Td
(the)Tj
1.474 0 Td
(effects)Tj
2.7212 0 Td
(of)Tj
1.0148 0 Td
(vari-)Tj
-35.5178 -1.2982 Td
(ous)Tj
1.6157 0 Td
(lapatinib)Tj
3.736 0 Td
(dosing)Tj
2.897 0 Td
(schedules)Tj
4.0422 0 Td
(on)Tj
1.2756 0 Td
(tumor)Tj
2.7439 0 Td
(growth)Tj
3.0727 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8199 0 Td
(1)Tj
0 g
(\).)Tj
1.2642 0 Td
(The)Tj
1.7801 0 Td
(goal)Tj
1.8766 0 Td
(of)Tj
1.0148 0 Td
(our)Tj
1.6214 0 Td
(work)Tj
2.279 0 Td
(is)Tj
0.8504 0 Td
(to)Tj
1.0261 0 Td
(determine)Tj
-32.9156 -1.2983 Td
(the)Tj
1.4683 0 Td
(best)Tj
1.8085 0 Td
(dosing)Tj
2.897 0 Td
(strategy)Tj
3.3278 0 Td
(given)Tj
2.3811 0 Td
(the)Tj
1.4683 0 Td
(observed)Tj
3.7928 0 Td
(toxicity)Tj
3.2031 0 Td
(limit.)Tj
2.3414 0 Td
(Specifically,)Tj
4.9152 0 Td
(we)Tj
1.3266 0 Td
(are)Tj
1.4514 0 Td
(interested)Tj
4.1612 0 Td
(in)Tj
-34.5427 -1.2983 Td
(answering)Tj
4.3199 0 Td
(the)Tj
1.474 0 Td
(question)Tj
3.6567 0 Td
(whether)Tj
3.4752 0 Td
(alternative)Tj
4.4221 0 Td
(dosing)Tj
2.8969 0 Td
(strategies)Tj
3.9232 0 Td
(can)Tj
1.6271 0 Td
(be)Tj
1.1508 0 Td
(applied)Tj
3.1521 0 Td
(to)Tj
1.0262 0 Td
(circumvent)Tj
4.7735 0 Td
(the)Tj
-35.8977 -1.3039 Td
(toxicity)Tj
3.1974 0 Td
(limit)Tj
2.1203 0 Td
(while)Tj
2.3697 0 Td
(exceeding)Tj
4.1896 0 Td
(the)Tj
1.4684 0 Td
(level)Tj
2.0126 0 Td
(of)Tj
1.0147 0 Td
(efficacy)Tj
3.2202 0 Td
(observed)Tj
3.7984 0 Td
(in)Tj
1.0375 0 Td
(continuous)Tj
4.7338 0 Td
(dosing)Tj
2.897 0 Td
(of)Tj
1.0148 0 Td
(lapatinib)Tj
-33.0744 -1.2982 Td
(while)Tj
2.3697 0 Td
(taking)Tj
2.7269 0 Td
(into)Tj
1.8425 0 Td
(account)Tj
3.3789 0 Td
(known)Tj
3.0047 0 Td
(characteristics)Tj
5.9074 0 Td
(of)Tj
1.0147 0 Td
(GBM)Tj
2.4095 0 Td
(growth)Tj
3.0727 0 Td
(and)Tj
1.7291 0 Td
(treatment)Tj
4.1386 0 Td
(response)Tj
3.7304 0 Td
(such)Tj
-35.3251 -1.2983 Td
(as)Tj
1.0148 0 Td
(diffusivity,)Tj
4.4446 0 Td
(intratumor)Tj
4.6658 0 Td
(heterogeneity,)Tj
5.879 0 Td
(and)Tj
1.7292 0 Td
(the)Tj
1.4683 0 Td
(blood)Tj
2.5172 0 Td
(brain)Tj
2.347 0 Td
(barrier.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 587.9055 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Materials)Tj
4.5071 0 Td
(and)Tj
1.989 0 Td
(methods)Tj
/F12 1 Tf
-6.4961 -1.4976 Td
(Cell)Tj
1.8803 0 Td
(culture)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 552.9259 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(SF268)Tj
2.6475 0 Td
(cells)Tj
1.9219 0 Td
(were)Tj
2.1203 0 Td
(obtained)Tj
3.736 0 Td
(from)Tj
2.2054 0 Td
(the)Tj
1.4683 0 Td
(National)Tj
3.6907 0 Td
(Cancer)Tj
3.084 0 Td
(Institute)Tj
3.583 0 Td
(\(NIH\))Tj
2.7439 0 Td
(and)Tj
1.7348 0 Td
(routinely)Tj
3.8608 0 Td
(grown)Tj
2.7949 0 Td
(in)Tj
-35.5915 -1.2982 Td
(DMEM)Tj
3.3108 0 Td
(supplemented)Tj
5.8507 0 Td
(with)Tj
2.0012 0 Td
(10%)Tj
1.9276 0 Td
(fetal)Tj
1.9105 0 Td
(bovine)Tj
2.9253 0 Td
(serum.)Tj
2.948 0 Td
(To)Tj
1.338 0 Td
(assess)Tj
2.5228 0 Td
(the)Tj
1.4683 0 Td
(effects)Tj
2.727 0 Td
(of)Tj
1.0148 0 Td
(drug)Tj
2.1146 0 Td
(treatment,)Tj
-32.0596 -1.3039 Td
(150,000)Tj
3.2995 0 Td
(cells)Tj
1.9162 0 Td
(were)Tj
2.1259 0 Td
(seeded)Tj
2.9084 0 Td
(on)Tj
1.2755 0 Td
(6-cm)Tj
2.2848 0 Td
(dishes)Tj
2.6929 0 Td
(and)Tj
1.7291 0 Td
(allowed)Tj
3.2881 0 Td
(to)Tj
1.0262 0 Td
(attach)Tj
2.6362 0 Td
(overnight.)Tj
4.3086 0 Td
(Cells)Tj
2.16 0 Td
(were)Tj
2.1203 0 Td
(then)Tj
-33.7717 -1.2983 Td
(switched)Tj
3.7303 0 Td
(to)Tj
1.0262 0 Td
(growth)Tj
3.0727 0 Td
(media)Tj
2.6929 0 Td
(supplemented)Tj
5.8563 0 Td
(with)Tj
1.9956 0 Td
(1%)Tj
1.4513 0 Td
(fetal)Tj
1.9106 0 Td
(bovine)Tj
2.931 0 Td
(serum)Tj
2.7212 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4684 0 Td
(indicated)Tj
3.9401 0 Td
(con-)Tj
-34.5257 -1.2983 Td
(centrations)Tj
4.6998 0 Td
(of)Tj
1.0148 0 Td
(lapatinib)Tj
3.7417 0 Td
(or)Tj
1.0941 0 Td
(DMSO)Tj
3.0728 0 Td
(\(vehicle\).)Tj
3.8947 0 Td
(Each)Tj
2.1714 0 Td
(treatment)Tj
4.1385 0 Td
(condition)Tj
4.1102 0 Td
(was)Tj
1.7008 0 Td
(done)Tj
2.228 0 Td
(in)Tj
1.0375 0 Td
(triplicate.)Tj
-32.9043 -1.3039 Td
(For)Tj
1.627 0 Td
(treatment)Tj
4.1329 0 Td
(discontinuation,)Tj
6.7748 0 Td
(cells)Tj
1.9219 0 Td
(were)Tj
2.1259 0 Td
(washed)Tj
3.1748 0 Td
(3)Tj
0.6973 0 Td
(times)Tj
2.3868 0 Td
(with)Tj
2.0012 0 Td
(media)Tj
2.6873 0 Td
(containing)Tj
4.5297 0 Td
(vehicle,)Tj
3.2145 0 Td
(and)Tj
-35.2741 -1.2982 Td
(then)Tj
2.0182 0 Td
(allowed)Tj
3.2882 0 Td
(to)Tj
1.0261 0 Td
(continue)Tj
3.7644 0 Td
(growth)Tj
3.0727 0 Td
(in)Tj
1.0375 0 Td
(media)Tj
2.6872 0 Td
(containing)Tj
4.5298 0 Td
(vehicle.)Tj
3.2144 0 Td
(Vehicle-treated)Tj
6.3496 0 Td
(cells)Tj
1.9219 0 Td
(were)Tj
2.1203 0 Td
(also)Tj
-35.0303 -1.2983 Td
(washed)Tj
3.1747 0 Td
(3)Tj
0.6974 0 Td
(times)Tj
2.3924 0 Td
(to)Tj
1.0204 0 Td
(control)Tj
3.1238 0 Td
(for)Tj
1.389 0 Td
(the)Tj
1.4683 0 Td
(effects)Tj
2.7269 0 Td
(of)Tj
1.0148 0 Td
(washing.)Tj
3.7304 0 Td
(Cell)Tj
1.7971 0 Td
(viability)Tj
3.4186 0 Td
(and)Tj
1.7291 0 Td
(cell)Tj
1.5591 0 Td
(death)Tj
2.4321 0 Td
(were)Tj
2.126 0 Td
(evaluated)Tj
-33.8001 -1.2983 Td
(by)Tj
1.1792 0 Td
(the)Tj
1.4683 0 Td
(trypan)Tj
2.846 0 Td
(blue)Tj
1.9275 0 Td
(exclusion)Tj
3.9855 0 Td
(assay)Tj
2.2677 0 Td
(using)Tj
2.3868 0 Td
(a)Tj
0.6576 0 Td
(ViCell)Tj
2.7609 0 Td
(cell)Tj
1.5591 0 Td
(viability)Tj
3.4128 0 Td
(analyzer)Tj
3.549 0 Td
(\(Beckman)Tj
4.286 0 Td
(Coulter\).)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 420.4346 cm
BT
/F12 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Mathematical)Tj
5.9858 0 Td
(modeling)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 211.9748 403.4267 cm
BT
/F13 1 Tf
1 TL
-0.004 Tc
0 0 Td
[()32()]TJ
1.1225 0 Td
[()-20()10()-2()8()]TJ
/F12 1 Tf
2.1373 0 Td
(cell)Tj
1.6327 0 Td
(dynamics.)Tj
/F7 1 Tf
5.0173 0 Td
(To)Tj
1.338 0 Td
(describe)Tj
/F6 1 Tf
3.5262 0 Td
[()12()]TJ
1.0148 0 Td
[()-13()14()7()20()]TJ
/F7 1 Tf
2.0466 0 Td
(cell)Tj
1.5591 0 Td
(dynamics,)Tj
4.2803 0 Td
(we)Tj
1.3266 0 Td
(designed)Tj
3.7644 0 Td
(a)Tj
0.6576 0 Td
(differential)Tj
4.6034 0 Td
(equa-)Tj
-35.223 -1.2982 Td
(tion)Tj
1.8424 0 Td
(model)Tj
2.744 0 Td
(of)Tj
1.0148 0 Td
(cell)Tj
1.559 0 Td
(growth)Tj
3.0727 0 Td
(given)Tj
2.3755 0 Td
(by)Tj
ET
Q
q
1 j
1 J
0 w
324.5102 367.7102 m
339.0236 367.7102 l
339.0236 367.3134 l
324.5102 367.3134 l
f*
10 0 0 10 324.5102 371.8488 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 335.5653 369.3543 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 327.5716 358.1858 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[()14()]TJ
/F15 1 Tf
1.4229 0.6859 Td
()Tj
/F6 1 Tf
1.0545 0 Td
[(\n )]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 363.1181 362.5511 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 373.9464 365.0456 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(1)Tj
/F15 1 Tf
0.7199 0 Td
( )Tj
ET
Q
q
1 j
1 J
0 w
391.0677 367.7102 m
400.6488 367.7102 l
400.6488 367.3134 l
391.0677 367.3134 l
f*
10 0 0 10 391.0677 371.8488 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 397.1338 369.3543 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 392.2582 358.1858 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[()]TJ
/F16 1 Tf
-2.5625 2.0919 Td
()Tj
3.4015 0 Td
()Tj
/F15 1 Tf
0.9524 -1.406 Td
( )Tj
/F6 1 Tf
0.9922 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 431.0929 362.5511 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 559.1622 365.0456 cm
BT
/F15 1 Tf
1 TL
0 0 Td
()Tj
/F7 1 Tf
(1a)Tj
/F15 1 Tf
()Tj
ET
Q
q
1 j
1 J
0 w
345.3732 327.4583 m
359.8866 327.4583 l
359.8866 327.0614 l
345.3732 327.0614 l
f*
10 0 0 10 345.3732 331.5401 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 356.3716 329.0456 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(2)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 348.4346 317.8771 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[()14()]TJ
/F15 1 Tf
1.4229 0.6859 Td
()Tj
/F6 1 Tf
1.0488 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 384.1511 322.2425 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 389.8771 324.737 cm
BT
/F15 1 Tf
1 TL
0 0 Td
( )Tj
/F6 1 Tf
0.9921 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 409.5496 322.2425 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(2)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 558.4251 325.7007 cm
BT
/F15 1 Tf
1 TL
0 0 Td
()Tj
/F7 1 Tf
(1b)Tj
/F15 1 Tf
()Tj
/F7 1 Tf
-0.004 Tc
-35.841 -2.6928 Td
(where)Tj
/F6 1 Tf
2.6476 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 232.4976 297.1275 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 238.2803 298.7716 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(and)Tj
/F6 1 Tf
1.7291 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 261.5811 297.1275 cm
BT
/F7 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(2)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 267.307 298.7716 cm
BT
/F7 1 Tf
1 TL
-0.004 Tc
0 0 Td
(denote)Tj
2.9536 0 Td
(the)Tj
1.4684 0 Td
(numbers)Tj
3.7757 0 Td
(of)Tj
1.0148 0 Td
(viable)Tj
2.5568 0 Td
(and)Tj
1.7291 0 Td
(dead)Tj
2.1317 0 Td
(cells,)Tj
2.143 0 Td
(respectively;)Tj
5.1136 0 Td
(the)Tj
1.4684 0 Td
(parameters)Tj
/F6 1 Tf
4.6771 0 Td
[(\n)]TJ
/F7 1 Tf
-35.7616 -1.2982 Td
(and)Tj
/F6 1 Tf
1.7292 0 Td
[()]TJ
/F7 1 Tf
0.7143 0 Td
(denote)Tj
2.948 0 Td
(the)Tj
1.4739 0 Td
(birth)Tj
2.1883 0 Td
(and)Tj
1.7292 0 Td
(death)Tj
2.4321 0 Td
(rates)Tj
2.1089 0 Td
(of)Tj
1.0148 0 Td
(viable)Tj
2.5512 0 Td
(cells;)Tj
/F6 1 Tf
2.1487 0 Td
[()]TJ
/F7 1 Tf
0.8617 0 Td
(denotes)Tj
3.3108 0 Td
(the)Tj
1.4684 0 Td
(carrying)Tj
3.5546 0 Td
(capacity)Tj
3.4752 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
/F6 1 Tf
1.4684 0 Td
[()12()]TJ
-36.1925 -1.2983 Td
[()-13()14()7()20()]TJ
/F7 1 Tf
2.0466 0 Td
(assay)Tj
2.2621 0 Td
(system;)Tj
3.1633 0 Td
(and)Tj
/F6 1 Tf
1.7291 0 Td
[()]TJ
/F7 1 Tf
0.5953 0 Td
(denotes)Tj
3.3052 0 Td
(the)Tj
1.474 0 Td
(clearance)Tj
3.9458 0 Td
(rate)Tj
1.7461 0 Td
(of)Tj
1.0148 0 Td
(dead)Tj
2.1317 0 Td
(cells.)Tj
/F12 1 Tf
-22.2177 -1.3039 Td
(Grid)Tj
2.1883 0 Td
(search)Tj
2.8743 0 Td
(algorithm)Tj
4.3879 0 Td
(for)Tj
1.4683 0 Td
(estimating)Tj
4.6432 0 Td
(model)Tj
2.8346 0 Td
(parameters.)Tj
/F7 1 Tf
5.7656 0 Td
(We)Tj
1.6044 0 Td
(implemented)Tj
5.5389 0 Td
(a)Tj
0.652 0 Td
(grid)Tj
1.8538 0 Td
(search)Tj
-35.0076 -1.2983 Td
(algorithm,)Tj
4.3824 0 Td
(given)Tj
2.3753 0 Td
(by)Tj
/F6 1 Tf
0 Tc
-1.2075 -2.0182 Td
[(\r)16()6()]TJ
1.2585 0 Td
[()18()12()]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 263.9055 218.0976 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[(\n)]TJ
/F17 1 Tf
(;)Tj
/F6 1 Tf
[()]TJ
/F17 1 Tf
(;)Tj
/F6 1 Tf
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 283.8614 226.6015 cm
BT
/F15 1 Tf
1 TL
0 0 Td
(f)Tj
/F6 1 Tf
[( )]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 298.7716 224.107 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(1)Tj
/F17 1 Tf
(;)Tj
/F6 1 Tf
[()13(\n)7()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 311.5275 226.6015 cm
BT
/F15 1 Tf
1 TL
0 0 Td
()Tj
/F6 1 Tf
[()]TJ
/F15 1 Tf
0.7313 0 Td
()Tj
0.6009 0 Td
( )Tj
/F6 1 Tf
0.9978 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 340.8377 224.107 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 344.3527 226.6015 cm
BT
/F15 1 Tf
1 TL
0 0 Td
()Tj
/F6 1 Tf
[(\n)]TJ
/F17 1 Tf
(;)Tj
/F6 1 Tf
1.3039 0 Td
[()]TJ
/F17 1 Tf
0.5272 0 Td
(;)Tj
/F6 1 Tf
0.4422 0 Td
[()]TJ
/F17 1 Tf
(;)Tj
/F6 1 Tf
0.8107 0 Td
[()]TJ
/F15 1 Tf
0.3458 0 Td
()Tj
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 386.3622 231.8173 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(2)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 392.0881 226.6015 cm
BT
/F15 1 Tf
1 TL
0 0 Td
()Tj
0.9921 0 Td
()Tj
/F6 1 Tf
[( )]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 411.9307 224.107 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(2)Tj
/F17 1 Tf
(;)Tj
/F6 1 Tf
[()13(\n)7()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 424.6299 226.6015 cm
BT
/F15 1 Tf
1 TL
0 0 Td
()Tj
/F6 1 Tf
[()]TJ
/F15 1 Tf
0.7313 0 Td
()Tj
0.6066 0 Td
( )Tj
/F6 1 Tf
0.9921 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 453.9968 224.107 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(2)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 457.4551 226.6015 cm
BT
/F15 1 Tf
1 TL
0 0 Td
()Tj
/F6 1 Tf
[(\n)]TJ
/F17 1 Tf
(;)Tj
/F6 1 Tf
1.3039 0 Td
[()]TJ
/F17 1 Tf
0.5329 0 Td
(;)Tj
/F6 1 Tf
0.4365 0 Td
[()]TJ
/F17 1 Tf
(;)Tj
/F6 1 Tf
0.8107 0 Td
[()]TJ
/F15 1 Tf
0.3458 0 Td
()Tj
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 499.4645 231.8173 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(2)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 502.9795 226.6015 cm
BT
/F15 1 Tf
1 TL
0 0 Td
(g)Tj
6.049 -0.3231 Td
()Tj
/F7 1 Tf
(2)Tj
/F15 1 Tf
()Tj
/F7 1 Tf
-0.004 Tc
-36.3455 -2.6362 Td
(which)Tj
2.6476 0 Td
(minimizes)Tj
4.4107 0 Td
(the)Tj
1.4683 0 Td
(squared)Tj
3.3732 0 Td
(distance)Tj
3.5036 0 Td
(between)Tj
3.5263 0 Td
(the)Tj
1.4683 0 Td
(observed)Tj
3.7984 0 Td
(and)Tj
1.7292 0 Td
(predicted)Tj
3.9968 0 Td
(cell)Tj
1.5646 0 Td
(numbers)Tj
3.7757 0 Td
(for)Tj
-35.2627 -1.3039 Td
(each)Tj
2.0296 0 Td
(experimental)Tj
5.4539 0 Td
(setting)Tj
2.8856 0 Td
(in)Tj
1.0318 0 Td
(order)Tj
2.4208 0 Td
(to)Tj
1.0261 0 Td
(estimate)Tj
3.549 0 Td
(model)Tj
2.7439 0 Td
(parameters)Tj
4.6715 0 Td
(that)Tj
1.7801 0 Td
(best)Tj
1.8085 0 Td
(recapitulate)Tj
4.8868 0 Td
(the)Tj
-34.2876 -1.2983 Td
(experimental)Tj
5.4595 0 Td
(results.)Tj
/F12 1 Tf
-4.2632 -1.2982 Td
(Characterizing)Tj
6.4459 0 Td
(the)Tj
1.542 0 Td
(relationship)Tj
5.2668 0 Td
(between)Tj
3.634 0 Td
(birth)Tj
2.33 0 Td
(and)Tj
1.7915 0 Td
(death)Tj
2.5569 0 Td
(rates)Tj
2.2393 0 Td
(and)Tj
1.7972 0 Td
(lapatinib)Tj
3.9797 0 Td
(dose.)Tj
/F7 1 Tf
2.9253 0 Td
(We)Tj
-35.7049 -1.2983 Td
(used)Tj
2.058 0 Td
(an)Tj
1.2019 0 Td
(exponential)Tj
4.8982 0 Td
(model)Tj
2.7383 0 Td
(to)Tj
1.0261 0 Td
(describe)Tj
3.5206 0 Td
(the)Tj
1.4683 0 Td
(relationship)Tj
4.989 0 Td
(between)Tj
3.5263 0 Td
(birth)Tj
2.194 0 Td
(and)Tj
1.7291 0 Td
(death)Tj
2.4263 0 Td
(rates)Tj
2.109 0 Td
(and)Tj
1.7291 0 Td
(lapa-)Tj
-35.6142 -1.3039 Td
(tinib)Tj
2.109 0 Td
(dose)Tj
2.0353 0 Td
(given)Tj
2.3811 0 Td
(by)Tj
/F6 1 Tf
0 Tc
8.6512 -1.8879 Td
[(\n)]TJ
/F15 1 Tf
()Tj
/F6 1 Tf
[()]TJ
/F15 1 Tf
()Tj
2.058 0 Td
()Tj
/F6 1 Tf
1.0488 0 Td
[(\n)]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 387.6094 110.6078 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(0)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 391.1244 113.1023 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 395.0929 116.7307 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[(\n)]TJ
ET
Q
q
1 j
1 J
0 w
5 0 0 5 397.9842 115.2566 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 400.9889 116.7307 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 404.674 113.1023 cm
BT
/F17 1 Tf
1 TL
0 0 Td
(;)Tj
/F15 1 Tf
15.4487 0.017 Td
()Tj
/F7 1 Tf
(3a)Tj
/F15 1 Tf
()Tj
/F6 1 Tf
-20.8174 -2.7665 Td
[()]TJ
/F15 1 Tf
0.5329 0 Td
()Tj
/F6 1 Tf
[()]TJ
/F15 1 Tf
()Tj
1.576 0 Td
()Tj
/F6 1 Tf
1.0488 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 387.5527 83.1118 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(0)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 391.0677 85.6062 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 395.0362 89.2346 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
5 0 0 5 398.0409 87.7606 cm
BT
/F14 1 Tf
1 TL
0 0 Td
(1)Tj
ET
Q
q
1 j
1 J
0 w
5.9998 0 0 5.9998 401.0456 89.2346 cm
BT
/F6 1 Tf
1 TL
0 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 404.7307 85.6062 cm
BT
/F17 1 Tf
1 TL
0 0 Td
(;)Tj
/F15 1 Tf
15.3693 0.017 Td
()Tj
/F7 1 Tf
(3b)Tj
/F15 1 Tf
()Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 169.285 23.6976 re
W* n
q
169.2283 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 338.0598 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Mathematic)Tj
5.0882 0 Td
(al)Tj
0.9779 0 Td
(modeling)Tj
4.2024 0 Td
(identifies)Tj
4.082 0 Td
(optimum)Tj
3.9968 0 Td
(lapatinib)Tj
3.8623 0 Td
(dosing)Tj
3.111 0 Td
(schedules)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
0.83 0.64 0.02 0 k
142.5827 34.9228 m
295.8236 34.9228 l
h
f*
0 g
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(Computationa)Tj
6.1229 0 Td
(l)Tj
0.4322 0 Td
(Biology)Tj
3.4371 0 Td
(|)Tj
0.83 0.64 0.02 0 k
0.4748 0 Td
(https:/)Tj
2.6788 0 Td
(/doi.org/10.13)Tj
6.0094 0 Td
(71/journal.p)Tj
5.1166 0 Td
(cbi.1005924)Tj
0 g
6.3497 0 Td
(January)Tj
3.7134 0 Td
(2,)Tj
1.0417 0 Td
(2018)Tj
26.9081 0 Td
(4)Tj
0.7654 0 Td
(/)Tj
ET
endstream
endobj
104 0 obj
<>stream
endstream
endobj
105 0 obj
<>stream
endstream
endobj
106 0 obj
<>stream
endstream
endobj
107 0 obj
<>stream
endstream
endobj
108 0 obj
<>stream
endstream
endobj
109 0 obj
<>stream
endstream
endobj
110 0 obj
<>stream
endstream
endobj
111 0 obj
<>stream
endstream
endobj
112 0 obj
<>stream
BT
66.402 0 Td
(24)Tj
ET
Q
endstream
endobj
113 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 115 0 R/Contents 116 0 R/TrimBox[0 0 612 792]>>
endobj
114 0 obj
<>stream
x]E;8,$.F6nzHKB=;ܡb}ꮮv7$@緿 @B !H$ @B !H$ @B !H$ @B !H$ @B !H$ @B !H$ @B !H$ @B !H$ @B !H$ @B !H$ @B !Gf˿9J"Os?i؉[a9I)u|.-`aXVVƢ*NR֬Bya*ZАM*B2R%`Q*bJx1b%HOOS*sLHw$q TFB_b*)9u^T\Rɉ08tA@!JH +2TEN[#M%Ŏ|P VK$#h5;-"/H$&2*i/Ņ*0`^`V-1ES\rV8 *e!}V"
л:R"hqKDxw6Cu\*E*P^/!rQb-:k|W*` 'ѩTQ1ȥ +>;q!TJ3ٜHD 齋)2c&IYE}3eu٬s6M[,-UL.՝*8h;dEJYGTJ}A-`YzE'|*ȥcz2):ީKҌlB)$0DX̂.=GBylRxYNu>e+<J|:Bt=SYՠʫ/E^dLEi18_|#a'{^|!6e)k4O=RiKd> a'OE^F."$E/:r922i٨*LyT`yr1 QwBq5M,bzIl\jlf٢5hoA+!KE/VEiV"܈sꬱ-&˟mAL(:u/%bSfnKž|j)HHr)8BT/11{ңم2NőS-uهוRұ텃:76ecߠ"gGKj+:SxTE'8F4hHAgAR_ZBHURu5)p4r+LlDC"IgDFV^BٱM #*XmyY\~Ř8ЉS&'s1?i
I$yar) LbD:#(x ~ELC5dĸ#ANE89yx/
DsPATLpIhɟĄ i,;`LTwZ/a.=%q
1# Ș*RJ/83HaE*`y
#xv|:OPN0w:Zl@k9_|ɴV؇t꾊)qa8X˸6M2=z$-9/9a?;27(bY/8*4Ԉ96J.I
m_^ aW˜&sHW'#Z:@TpcĜ11OCQ gE yS٦t x$inݧ|Q)Y0T.Hp;h8A˺sYy3ڸ(TP2h(e1]ˎ}JxVa%ΚsJM|x0[UZ",DphՈԈR>PK) Cu:aZd젅klGCUǖ"ZX'U4X'47%EՉ1D#O,ʹå0# zLHWQ0qBG:NI̒:_-gxRJ*$l&AJvܟwENK%;], 1@fi>55
HȚH8ArJ:w>xajKDaɚ4/
Bif뗊)
"B*HÄ`HWA`B% "Ԣ+@YSPq܁K.uv6BIqUay )Dd.YQp0S I"0ɯpJ%51b>/s:"3N/{waP -QIˬޙb4$d4HW&p