MTN-001: Unique Contributions. Craig W. Hendrix, M.D. Johns Hopkins University Baltimore, MD USA

Transcription

1 MTN001: Unique Contributions Craig W. Hendrix, M.D. Johns Hopkins University Baltimore, MD USA

2 Unique Contributions o Compare oral v. vaginal product adherence o Impact of second product on adherence o Comparison of oral v. vaginal PK o Integrated multicompartment PK model after oral dosing (blood cells, tissue, lumen) o Additive effect of dual route dosing o Comparison of observed v. unobserved PK to assess adherence o Simulation of VOICE tissue intracellular TDP kinetics

3 Adherence

4 Importance of Adherence Adherence Pharmacokinetics Distribution/clearance Pharmacodynamics Toxicodynamics HIV Infection HIV Exposure Viral Kinetics Distribution/clearance Viral Dynamics Infectivity (Toxicity) Behaviors Particles in Space & Time Interactions of Drug, Host, Virus

5 Importance of Adherence o Carraguard Trial o N=6202 o Seroconversion: no significant difference Active: 134 Placebo: 151 o Adherence 43%

6 Adherence/Acceptability Objectives o To compare adherence to and acceptability of three daily regimens of tenofovir (oral, vaginal, and dual use) o To identify factors associated with product adherence, and whether these differ when women use one of three daily regimens of tenofovir (oral, vaginal, and dual use) o To examine whether sexual activity or male condom use varies when women use one of three daily regimens of tenofovir (oral, vaginal, and dual use) o To assess the timing of product use with sexual intercourse o To determine the level of sharing of study products with nonparticipants (and to assess with whom products are shared)

7 Pharmacokinetics

8 Tenofovir Disoproxil Fumarate Tenofovir (PMPA; prodrug) Disoproxil (absorption) Fumarate (formulation) TDF: Inactive prodrug; only active after modification inside cells

9 Tenofovir Diphosphate Cellular kinase Cellular kinase Tenofovir (inactive) Tenofovir monophosphate (inactive) Tenofovir diphosphate (active) Intracellular Extracellular TDP: tenofovir diphosphate is active form; 2 phosphates added inside cells TDF: Inactive prodrug; only active after modification inside cells

10 Tenofovir Pharmacokinetics 1000 Blood Plasma: t 1/2 17 h Oral Prodrug of Active Diphosphate Cellular kinases add 2 phosphates PMPA ng/ml Vaginal Blood PBMCs t 1/2 60 >175h LLOQ Hours BarditchCrovo AAC 2001, Mayer JAIDS 2006; Hawkins JAIDS 2005

11 Definitions: PK & PD o Pharmacokinetics (PK) Body effect on the drug Varying in drug conc n in space and time Concentrationtime data Hitting the target o Pharmacodynamics (PD) Drug effect on body/pathogen Variation of drug effects with varying drug amount Concentrationresponse Deciding on the target 6 Concentration Pharmacologic Effect Efficacy Toxicity Time Log Concentration

12 PD: Selecting Target Pharmacodynamics Seroconverters 1.0 Probability of Likelihood of Seroconversion Seroconversion 0.5 NonSeroconverters Concentration TDP Intracellular Trough (C min ) Concentration Pharmacokinetics

13 Site of Action 4 L/DC Cellfree HIV 1 Cellassociated HIV 1 2 Drug DC 7 Lumen Mucosa Lamina Propria Blood/Lymph

14 Drug Compartments Topical Dose Oral Dose Lumen Tissue Blood

15 Drug Compartments Topical Dose Oral Dose Lumen Tissue Blood Concentration Distance

16 Drug Compartments Topical Dose Oral Dose Lumen Tissue Blood CD4+ Cells TFVàTFVpp CD4+ Cells TFVàTFVpp

17 Drug Compartments Topical Dose Oral Dose Lumen Tissue Blood CD4+ Cells TFVàTFVpp CD4+ Cells TFVàTFVpp

18 PK Model Building Ideal Blood Cervicovaginal Tissue Vaginal Lumen Oral Dosing IS IC Vaginal Dosing Resistance? IS IC Efficacy

19 PK Model Building Feasible Blood Blood Cervicovaginal Vaginal Plasma PBMC Tissue Lumen Sparse Sites Intensive Sites

20 Intensive PK Sampling *Sequence

21 Sparse PK Sampling 1, 2* 3, 4* 5, 6* 1, 2* 3, 4* 5, 6* *Sequence

22 PK MultiSite Model Building Blood Blood Cervicovaginal Vaginal Plasma PBMC Tissue Lumen Sparse Sites Intensive Sites

23 Complementary PK Sampling o Traditional Intensive Sampling Few Subjects, Many Times Peak Previous Dose AreaunderCurve Trough o Sparse Sampling (Population PK) Many Subjects, Few Times

24 Value of PK Data After MTN001 o Duration of concentration dose frequency? CoitallyDependent Dosing? o Route of Dosing Oral or Topical most efficient? o PKPD Modeling in Efficacy Studies What concentrations are associated with efficacy?

25 Dose & Frequency? 350 HIV Suppressive Concentration? Relative Concentration TFV plasma single dose TFV IC single dose Days HIV HalfLife?

26 CoitallyDependent v. Daily HIV Suppressive Concentration? Relative Concentration TFV IC single TFV IC 0,24 Weekly TFV IC multiple Days HIV HalfLife?

27 VOICE: Ideal Finding Identification of Critical concentration of active drug at site of action provides guidance for interpretation of results and planning future ARV studies Pharmacodynamics Seroconverters Probability of Likelihood of Seroconversion Seroconversion NonSeroconverters Concentration TDP Intracellular Trough (C min ) Concentration Pharmacokinetics

28 PKPD: VOICE Alone Topical Oral 1.0 Lumen 5 CD4+ Cells TFVàTFVpp 6 Tissue 3 CD4+ Cells TFVàTFVpp 4 Blood 1 CD4+ Cells TFVàTFVpp 2 VOICE Seroconversion Likelihood of Seroconversion Concentration [CD4+ Tenofovir Diphosphate] Pharmacokinetic Pharmacodynamic Link

29 PKPD: VOICE & MTN001+ Topical Oral 1.0 Lumen 5 CD4+ Cells TFVàTFVpp 6 Tissue 3 CD4+ Cells TFVàTFVpp 4 Blood 1 CD4+ Cells TFVàTFVpp 2 VOICE Seroconversion Likelihood of Seroconversion Concentration [CD4+ Tenofovir Diphosphate] Pharmacokinetic Pharmacodynamic Link

30 Unique Contributions o Compare oral v. vaginal product adherence o Impact of second product on adherence o Comparison of oral v. vaginal PK o Integrated multicompartment PK model after oral dosing (blood cells, tissue, lumen) o Additive effect of dual route dosing o Comparison of observed v. unobserved PK to assess adherence o Simulation of VOICE tissue intracellular TDP kinetics

31 Questions?

32 Tenofovir PK Data Sources Study PK Data Available # on Drug Route Fluid Blood Cellular PK Tissue PK Tissue Cellular PK HIV > + HPTN 050 Published 25 V B HPTN 057 Q O B,BM,CB (60)* HPTN 059 Q V B 14 CTFV Q O B CD4 R CD4 3 CONRAD TFV Q V B PBMC V 2 MMC 2,3 MTN 002 Q V B,CB,A PBMC V 2,U MTN 001 Q V,O B PBMC V 2 MMC 3 CAPRISA 004 Q V B PBMC V 2 V,Cx 3 68 CDC PrEP Q O B PBMC 125 MTN 006 Q R,O B PBMC R 2 MMC 3 MTN 003 Q V,O B Vertical transmission; 2 Uncertain source of cells (cytobrush, biopsies) 3 Uncertain sensitivity (MMC vagina, MMC colon, CD4 colon)