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The model was combined with data from the literature for the \ antiviral interferon and used to predict the outcome of several Phase Ib \ trial designs for a Merck HCV NS3/4A protease inhibitor (PI). After the trial \ was completed and the data unblinded, a segmented regression model was \ constructed to allow nonlinear least squares fitting of viral load of all the \ patients simultaneously. It became obvious that the fitted model needed \ several changes to account for the pharmacokinetics of the PI and the \ emergence of resistance mutants that had not been anticipated prior to the \ trial. Interactive exploration of model and parameter values allowed us to \ quickly revise the kinetic model and refit it. Lastly, we used Monte Carlo \ methods to generate a large cohort of virtual patients, and visualization of \ the outcome of the simulated trial demonstrated that the model was able to \ predict the median and range of response to treatment in a dose-proportional \ way." }], "ItemParagraph", CellChangeTimes->{ 3.448729439002983*^9, {3.4565846302412577`*^9, 3.4565846615846066`*^9}, { 3.456584828582469*^9, 3.4565848650663767`*^9}, {3.456584915659479*^9, 3.4565849444716105`*^9}, {3.4565995215*^9, 3.456599582359375*^9}, { 3.456599616609375*^9, 3.456599703*^9}, {3.456599872890625*^9, 3.456600119203125*^9}, {3.45660022153125*^9, 3.456600274015625*^9}, { 3.45660031909375*^9, 3.456600350125*^9}, {3.456600392*^9, 3.456600397265625*^9}, {3.45660047275*^9, 3.456600497328125*^9}, 3.45660053940625*^9, {3.4566007455*^9, 3.456600795875*^9}, { 3.4566148370108604`*^9, 3.456615005336831*^9}, {3.456615082335845*^9, 3.4566151273977685`*^9}, {3.4566153272233353`*^9, 3.4566155047679377`*^9}, {3.4566155545485506`*^9, 3.4566157661239676`*^9}, {3.456615824029476*^9, 3.456616006943735*^9}, { 3.4566160955962734`*^9, 3.456616162636533*^9}, {3.4566162358807507`*^9, 3.4566163164932957`*^9}, {3.4566163596980796`*^9, 3.456616428263212*^9}, { 3.4566164993909435`*^9, 3.4566165637362986`*^9}, {3.4566167080497217`*^9, 3.4566167888939896`*^9}, {3.45661683586304*^9, 3.456616876003419*^9}, { 3.456616944518605*^9, 3.4566170320492945`*^9}, {3.4566170642834635`*^9, 3.4566171405486*^9}, {3.456617206860676*^9, 3.456617245344805*^9}, { 3.456617444202907*^9, 3.4566174542497177`*^9}, {3.4566174920619755`*^9, 3.4566175474988155`*^9}, {3.456617728558998*^9, 3.456617729980855*^9}, { 3.45661782097969*^9, 3.456617836260744*^9}, {3.456617973133992*^9, 3.456617997227434*^9}, {3.4566180703202486`*^9, 3.4566180733827095`*^9}, { 3.4566181523191986`*^9, 3.4566181587253666`*^9}, {3.4566182693177013`*^9, 3.4566182923330317`*^9}, 3.457946128555988*^9, {3.457946182360222*^9, 3.4579462407575006`*^9}, 3.465390236703125*^9, 3.465390278984375*^9, { 3.46539038715625*^9, 3.465390420984375*^9}, {3.46539045934375*^9, 3.4653905869375*^9}}, LineSpacing->{2, 0}] }, Open ]] }, Open ]], Cell[CellGroupData[{ Cell["", "SlideShowNavigationBar", CellTags->"SlideShowHeader"], Cell[CellGroupData[{ Cell["Introduction", "Section", CellChangeTimes->{{3.463138701633875*^9, 3.463138709227625*^9}}], Cell[CellGroupData[{ Cell["\<\ Essentially, all models are wrong, but some are useful. \[LongDash] George E. \ P. Box [1]\ \>", "Item", CellChangeTimes->{{3.4635678591875*^9, 3.463567869671875*^9}, { 3.46356796171875*^9, 3.463567997296875*^9}, {3.4635688845625*^9, 3.4635688845625*^9}}, CellTags->"George Box"], Cell["\<\ The models should be based on the biology, chemistry, and/or physics of the \ problem\ \>", "Item", CellChangeTimes->{{3.463568887171875*^9, 3.46356891603125*^9}, { 3.463569026859375*^9, 3.463569026859375*^9}}], Cell[CellGroupData[{ Cell[TextData[{ "That is, we are ", StyleBox["not", FontSlant->"Italic"], " curve fitting" }], "Subitem", CellChangeTimes->{{3.463569038578125*^9, 3.463569057015625*^9}}], Cell["\<\ The model should be able to explain or predict a non-intuitive result\ \>", "Subitem", CellChangeTimes->{{3.463569089171875*^9, 3.463569135796875*^9}, 3.46372935159375*^9}] }, Open ]], Cell["\<\ The models need only capture the essential features of the experiment \ (clinical trial) under investigation\ \>", "Item", CellChangeTimes->{{3.46356822253125*^9, 3.463568275765625*^9}, { 3.463568933015625*^9, 3.46356893334375*^9}}], Cell["\<\ Our models and the simulations derived therefrom are used to help make \ informed decisions\ \>", "Item", CellChangeTimes->{{3.463568299671875*^9, 3.463568344453125*^9}, 3.4637293606875*^9}], Cell[CellGroupData[{ Cell["Is the treatment effective?", "Subitem", CellChangeTimes->{{3.4635683840625*^9, 3.4635683916875*^9}}], Cell["What is the best sampling strategy?", "Subitem", CellChangeTimes->{{3.463568399796875*^9, 3.4635684176875*^9}}], Cell["What is the most effective dose that is still safe?", "Subitem", CellChangeTimes->{{3.463568418859375*^9, 3.4635684323125*^9}}] }, Open ]], Cell["\<\ This presentation will describe some of the work that was done to design and \ analyze a Phase 1b clinical trial for Merck's hepatitis C protease inhibitor \ MK-7009\ \>", "Item", CellChangeTimes->{{3.463861305828125*^9, 3.46386138603125*^9}}] }, Open ]] }, Open ]] }, Open ]], Cell[CellGroupData[{ Cell["", "SlideShowNavigationBar", CellTags->"SlideShowHeader"], Cell[CellGroupData[{ Cell["Hepatitis C", "Section", CellChangeTimes->{{3.463138741383875*^9, 3.4631387496495*^9}, { 3.463831464475236*^9, 3.463831466287121*^9}}], Cell[CellGroupData[{ Cell["World Health Organization [2]", "Subsection", CellChangeTimes->{{3.4638317121419835`*^9, 3.4638317207350187`*^9}}], Cell[CellGroupData[{ Cell["\<\ Hepatitis C virus (HCV) is one of the viruses (A, B, C, D, and E), which \ together account for the vast majority of cases of viral hepatitis. \ \>", "Item", CellChangeTimes->{{3.4638314474185233`*^9, 3.4638314848433247`*^9}, { 3.4638315275475845`*^9, 3.463831531561847*^9}, {3.4638315745004025`*^9, 3.4638315782178907`*^9}, {3.463831610759794*^9, 3.463831610759794*^9}}], Cell["\<\ Globally, an estimated 170 million persons are chronically infected with HCV \ and 3 to 4 million persons are newly infected each year. \ \>", "Item", CellChangeTimes->{{3.4638314474185233`*^9, 3.4638314848433247`*^9}}], Cell[CellGroupData[{ Cell["\<\ About 80% of newly infected patients progress to develop chronic infection.\ \>", "Subitem", CellChangeTimes->{{3.463831790557334*^9, 3.463831830647748*^9}}], Cell["\<\ Cirrhosis develops in about 10% to 20% of persons with chronic infection.\ \>", "Subitem", CellChangeTimes->{{3.463831790557334*^9, 3.4638318433185687`*^9}}], Cell["\<\ Liver cancer develops in 1% to 5% of persons with chronic infection over a \ period of 20 to 30 years.\ \>", "Subitem", CellChangeTimes->{{3.463831790557334*^9, 3.463831844771573*^9}}] }, Open ]], Cell["\<\ HCV is spread primarily by direct contact with human blood. The major causes \ of HCV infection worldwide are use of unscreened blood transfusions, and \ re-use of needles and syringes that have not been adequately sterilized.\ \>", "Item", CellChangeTimes->{{3.4638314474185233`*^9, 3.4638314848433247`*^9}, { 3.4638315275475845`*^9, 3.4638315275475845`*^9}}], Cell["No vaccine is currently available to prevent hepatitis C.", "Item", CellChangeTimes->{{3.4638314474185233`*^9, 3.4638314848433247`*^9}, { 3.4638315275475845`*^9, 3.463831531561847*^9}}], Cell["\<\ Humans and chimpanzees are the only known species susceptible to infection, \ with both species developing similar disease.\ \>", "Item", CellChangeTimes->{{3.4638314474185233`*^9, 3.4638314848433247`*^9}, { 3.4638315275475845`*^9, 3.463831531561847*^9}, {3.4638315745004025`*^9, 3.4638315782178907`*^9}, 3.463831610759794*^9, {3.4638316575683994`*^9, 3.4638316860347805`*^9}}], Cell["\<\ An important feature of the virus is the relative mutability of its genome, \ which in turn is probably related to the high propensity (80%) of inducing \ chronic infection.\ \>", "Item", CellChangeTimes->{{3.4638314474185233`*^9, 3.4638314848433247`*^9}, { 3.4638315275475845`*^9, 3.463831531561847*^9}, {3.4638315745004025`*^9, 3.4638315782178907`*^9}, 3.463831610759794*^9, {3.4638316575683994`*^9, 3.463831660396289*^9}, {3.4638317033927116`*^9, 3.463831704392628*^9}}] }, Open ]] }, Open ]] }, Open ]] }, Open ]], Cell[CellGroupData[{ Cell["", "SlideShowNavigationBar", CellTags->"SlideShowHeader"], Cell[CellGroupData[{ Cell["Hepatitis C Virus Infection", "Section", CellChangeTimes->{{3.463138741383875*^9, 3.4631387496495*^9}}], Cell[TextData[Cell[BoxData[ FormBox[GridBox[{ {Cell[GraphicsData["Metafile", "\<\ CF5dJ6E]HGAYHf4PEfU^I6mgLb15CDHPAVmbKF5d0@001AR/0@0006`0002D0P00k`<0024;00322P00 i`T008X@000Z;`00^2d00215CDH00040[1P50:<000020000000000000000000091<0000I003?0000 3`40000000000000000004TZ0`1E8P@0AP0002`0000P0000ADe6:`500@0L00004000008@`=/00000 F08005P200160000G00005000015CDH[8T0400`0000000007T0900`000000000940100`000000000 <4020100000400000020?b501`0<0000000000A0000<0000000004H0000X0000700004M4BD<20000 F0800>P3000R2`00``X0000000160000:00001`00017A4U30P000>L2003^0`008`/00<@:00000000 AP000013003d@P00ADe6:bY0000T000060000000P3l000200000P000P3l000200000P0Q000EX@P00 G480008@`=/100000000000000000000000000400029D4i73@XJ2P0000e9B4AB0001X@000EX80`00 080S4RX000<0D4aDA@000800002008200000P800P020P820P<30`?l0003o0?oo0000ool0o`3ooooo o`000000000000000000000000000000000000000000000000000000000000000000000000000000 000000000000000000000000<`00IP00V@00c000o`0c000c<`0cIP0cV@0cc00co`1V001V<`1VIP1V V@1Vc01Vo`2I002I<`2IIP2IV@2Ic02Io`3<003<<`3I03>I IIS>IVC>Ic3>Ioc?<03?<Doooooooooooooooooooool09JfIHP00005RBdM408P57DP0000mY@TJl3@GIPLI:C:_7^E]fCV:0HF1>M :PFgK^2cPGN3UJ19MP9Mo`57Jk]:U371dO`7DXTh:]:J^LocMP=XH=3XKZ11SRa2EA@o<8g6noCkdNmG Ok0ML^EITRII?VB8Vllj:?3140ZUBOY;UZM9WYnAUWUjDSc_7m7[Xo@VWfFR02B:nfnNCm9^>8KmlOXLWfC2=dnWZkCFh<^Y5@6X1@ G_3@jNUVVf@SCO2m7kHo@/WV_>0Qf0/gDVj/YM@OXCB]a=cja]hN2j01]Qa1>MFZj4ej8nC6PZPo3l72 c[O[efL0jNc6f1h;Wfd@3nEIVP:El/ZD0KLnnlO=KVP_488G;/^ba;3JlWBB`R]gHlN=Qdl83bDoWKgN d<=CdcW0k6HW=2I0oU8^N@5mXia`=fK1Z90d1_Ne5=:Oa;ncOG?S9ke:N?0/ChCbi9GJWYjmf[cIgS3A 5J;TSM2fM21/KX8=E`R@;`mUjI/BXKkU^/QCf0B6`cK[@A0bXIWoWCf/JgcL1eS41l[DD `3>@INOW57E[^^GPBa2CHW;dP@5UBfGK[MbF?9:O]:Hk4I<:;gaCO 5coAn87C?/>ohLB=XY>jhg@]Q9cniB:QOF>A@j^6@dJ2blROie?YRb=nnbN2=5l:b0jghld4/Dgd1VS [6Ao6DWA:_>8]4Kj8PBnfFbA4RcFMclIkooB[S]1U6_QVhii/`1XI< 7W?6R^i3XR48VLHg]gJCdKM5fU83k`jQeWEm5]F:To1e70FQ;3ToUcBPlBCN_UQZ@m459`F250>Qk?1< Y`6=/C>j]Qg>D30/WloQU@RAMQ4@bQ>a^MF4hPTjn/Rd=jf_TQf9aX>71DSn:RT2@RPhURbPlAIm_FT37Wm57ldcK9GlWQD3XM;olaY^kUh8RDlI?VCaKg5g4b86o5idkni2B[FGAQZ>47`n AR0R/=@;dVUSPo?P9VHJ@ 49SeGaj3RMJOPHOFWof?o7J?;cQU^VLg725Jf5DnZTnX2;j8h5e1ie^L2d;2@oP:T?jfDScdhinfojK8 fn/[kkHI8R04ljgPX[>=`m@G]N?Vk42:2Pl9991bi9icO?g;mm^gOeU/Ggflidb4BB?jIgoS20RARCH/ UTA]A2L;RF/ZUV@[GnVEI8GLnWkm5Ol7a`2ZcClF16cm4ECAEo]/:nRgd6Tj[C35@4PkNi1?mlA^Jl>o Fb^a36BCc]];?KCnm;lPj<0mj`OPYMXK`33:U^`UCjJ7e ;Jf1O_PGC0JUVB3ZgXG;YQoR88C/[5;ii`agH^MIDRFSeCHZSD`mm97`d7KmjNnnQdkRmMg3DAlNKG0; 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This is due to the presence \ of less fit mutant variants in the initial population of virions at about \ 0.01 %. These mutants are not as susceptible to the treatment as the \ wild-type virions, and as the wild-type population declines, the mutant \ population expands.\ \>", "ItemParagraph", CellChangeTimes->{{3.46347009759375*^9, 3.463470123*^9}, { 3.46347020171875*^9, 3.463470357359375*^9}, {3.463470403859375*^9, 3.463470529734375*^9}, {3.46347057553125*^9, 3.4634705928125*^9}, { 3.463474622719983*^9, 3.463474644001506*^9}, {3.4635130971875*^9, 3.463513133703125*^9}, 3.463729458375*^9, 3.464440805391321*^9}], Cell["\<\ Here are 2 examples showing typical data for low and high doses. 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