Applied Population Pharmacokinetic / Pharmacodynamic Modeling

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  • Applied Population Pharmacokinetic / Pharmacodynamic Modeling of Antiretroviral and Antimalarial Drug Therapy

    Da ni el R sha mm a r2009

    Department of PharmacologyInstitute of Neuroscience and Physiology

    The Sahlgrenska Academy at University of GothenburgSweden

  • Printed by Intellecta Infolog AB, V Frlunda, Sweden

    Cover illustration by Kristoffer Sderqvist

    Daniel Rshammar 2009

    ISBN 978-91-628-7667-8

  • The White Rabbit put on his spectacles. Where shall I begin, please your Majesty? he asked. Begin at the beginning, the King said, very gravely, and go on till you come to the end: then stop.

    Lewis Carrol

    To S chr umfe n

  • abst r act

    hiv/aids and malaria are two major global infectious diseases. Although better drugs against these conditions are becoming more available, dosages may not always be opti-mal with respect to effectiveness, safety, cost or convenience of administration. This thesis aims to quantitate the pharmacological relationship between dosing history, sources of variation between individuals, drug exposure and response to selected antiretroviral and antimalarial regimens.

    Pharmacometric, i.e. pharmaco-statistical, models were fitted to observed data from five clinical studies, using the nonmem software. Several polymorphic genes coding for drug metabolizing enzymes and transporters were found to have impact on the disposition of the non-nucleoside reverse transcriptase inhibitor efavirenz in healthy Ugandan subjects after single dose administration. Moreover, using simulation it was demonstrated that a 200 mg dose reduction in Zimbabwean hiv-patients with genetically decreased metabolic capacity would maintain efavirenz exposure within the therapeutic range during repeat-ed administration. In a typical clinical trial large amounts of drug response data are col-lected. However, usually only limited amounts of the recorded data are actually used for investigating differences between regimens. Herein, a drug-disease model was developed to describe the time-course of repeatedly measured hiv-rna levels in Scandinavian pa-tients randomized to one of three commonly prescribed antiretroviral regimens. The ini-tial analysis showed that an efavirenz-containing regimen appeared to be more efficacious compared to two protease inhibitor-containing regimens. Antimalarial artemisinin-based combination therapy bears many resemblances to antiretroviral treatment. The drugs ex-hibit variable and complex pharmacokinetics and the diseases themselves bring reasonable possibilities for pharmacodynamic assessment. Auto-induction of drug metabolism was described after multiple dosing with artemisinin in Vietnamese patients. The frequency of recrudescent malaria infection was as high as 37% but could not directly be linked to low artemisinin exposure. The elimination half-life of piperaquine, a suitable partner drug for artemisinin-based combination treatment, was estimated to 12 days with large between-subject variability.

    The thesis demonstrates the utility of pharmacometric methodology in the analysis of clinical data originating from high-income countries as well as resource-limited settings. Ultimately it can be a tool for decision analysis and policy making.

    Keywords : hiv, malaria, pharmacokinetics, pharmacodynamics, pharmacometrics, nonmem

    Applied Population Pharmacokinetic / Pharmacodynamic Modeling of Antiretroviral and Antimalarial Drug Therapy

  • swedish summary populrvetenskaplig sammanfattning

    hiv och malaria r tv infektionssjukdomar som orsakar stort individuellt lidande med ptagliga ekonomiska konsekvenser runt om i vrlden. Den hr avhandlingen syftar till att med hjlp av farmakokinetiska och farmakodynamiska modeller beskriva det farma-kologiska sambandet mellan dosering, variabilitet mellan individer (pga. vikt, kn, njur-funktion, gener, sjukdom etc.), lkemedelsexponering och effekt av behandling mot dessa tillstnd.

    Med farmakokinetik avses vetenskapen om hur lkemedel omstts (absorberas, frdelas, bryts ner samt utsndras) i kroppen. Farmakodynamik r det forskningsomrde inom vilket sambandet mellan exponering av ett lkemedel och dess farmakologiska effekt/biverkan studeras. Tiden till effektens intrdande, dess grad och duration r direkt eller indirekt relaterad till lkemedelshalten i blodet. Genom att anpassa matematiska och statistiska modeller till experimentellt observerade data kan interaktionen mellan lkemedelskoncentration, effekt och sjukdomsfrlopp beskrivas kvantitativt. Sdana, s kallade farmakometriska modeller, kan anvndas fr att optimera nuvarande lkemedelsterapier eller fr att avgra lmpliga doseringsrekommendationer fr nya behandlingar.

    Betydelsen av genetiska skillnader mellan individer fr omsttningen av hiv-lkemedlet efavirenz undersktes i friska frskspersoner frn Uganda. Vidare studerades patienter frn Zimbabwe fr att avgra om personer med smre frmga att omstta efavirenz br administreras en lgre dos fr att, med bibehllet behandlingsresultat, minska risken fr biverkan. Sambandet mellan antiretroviral lkemedelsterapi och virusniver beskrevs efter upprepade mtningar i skandinaviska hiv-patienter som inte tidigare sttt under be-handling. Drutver har de farmakokinetiska och farmakodynamiska egenskaperna fr de tv malarialkemedlen piperakin och artemisinin beskrivits i tv asiatiska populationer.

    Bde kn och genetik visade sig pverka farmakokinetiken av efavirenz. En dossnkning frn 600 till 400 mg dagligen freslogs vara mjlig i patienter med dlig kapacitet att bryta ner efavirenz. En kombinationsbehandling innehllande efavirenz visade sig vara effektivare n tv andra vanligt frekommande behandlingar. Artemisinin gav som vntat inte tillrckligt god effekt nr det gavs som monoterapi till vietnamesiska vuxna och barn. Piperakin skulle kunna vara en lmplig partner till artemisinin i kombinationsbehandling mot malaria, men dess lnga terminala halveringstid br tas i beaktande d resistenta parasiter kan uppst vid otillrckliga lkemedelsniver.

    Sammanfattningsvis beskriver detta arbete hur farmakometriska modeller r anvndbara verktyg fr att sammanfatta och utvrdera lkemedelsdata som inhmtats svl i Skandinavien som i vrldens fattigare lnder. Fretrdesvis br denna metodik ka fr att p ett kostnadseffektivt tillvgagngsstt erhlla verkningsfullare och skrare behandlingsalternativ.

    Farmakokinetisk och farmakodynamisk populationsmodellering av lkemedel fr behandling av hiv och malaria

  • Papers Discussed

    This thesis is based on the following papers, which will be referred to in the text by Roman numerals.

    Mukonzo J, Rshammar D, Waako P, Andersson M, Fukasawa T, Milani L, I. Svensson J-O, Ogwal-Okeng J, Gustafsson LL, Aklillu E (2008) A novel poly-morphism in MDR1 gene, CYP2B6*6 and sex predict single dose efavirenz population pharmacokinetics in Ugandans. Submitted

    Nyakutira C, Rshammar D, Chigutsa E, Chnozi P, Ashton M, Nhachi C, II. Masimirembwa C (2008) High prevalence of the CYP2B6 516GT(*6) variant and effect on the population pharmacokinetics of efavirenz in hiv/aids outpatients in Zimbabwe. Eur J Clin Pharm 64: 357-365

    Rshammar D, Josephson F, Simonsson USH, Ekvall H, Flamholc L, III. Ormaasen V, Snnerborg A, Wallmark E, Ashton M, Gissln M (2009) Assessment of antiretroviral drug efficacy in the northiv study by non-linear mixed effects modeling. Manuscript

    Rshammar D, Hai TN, Thanh NV, Huong DX, Huong NV, Thu NB, Ashton M IV. (2007) Modeling of the time-dependent population pharmacokinetics and exposure-response relationship of the antimalarial artemisinin based on sparsely sampled saliva. Manuscript

    Rshammar D, Hai TN, Friberg Hietala S, Huong NV, Ashton M (2006) Pharmaco-V. kinetics of piperaquine after repeated oral administration of CV8 in 12 healthy male subjects. Eur J Clin Pharm 62: 335-41

    Reprints were made with kind permission from Springer

  • Table of Contents

    Introduction .............................................................................................................................................11

    Background ......................................................................................................................................11 The diseases .......................................................................................................................................12 HIV/AIDS ....................................................................................................................... 12 Malaria ............................................................................................................................ 13 Drug therapy ....................................................................................................................................14 Antiretroviral drugs ........................................................................................................ 14 Antimalarial drugs ......................................................................................................... 16 Pharmacokinetic and pharmacodynamic non-linear mixed effects models ...........17 Regression models ............................................................................................................ 17 The structural model ( fixed effects model) .................................................................... 17 The individual model (mixed effects model) ................................................................ 18 Covariates ........................................................................................................................ 18 Drug-disease models and simulation ............................................................................ 20

    Aims of the Thesis ........................................................................

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