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Jenell Coleman, MD MPH 1 , Ayyappa Chaturvedula PhD 2 , Craig Hendrix, MD 1

EFFECTS OF HORMONAL CONTRACEPTION ON TENOFOVIR PHARMACOKINETICS: An Exploratory Secondary Data Analysis of MTN-001. Jenell Coleman, MD MPH 1 , Ayyappa Chaturvedula PhD 2 , Craig Hendrix, MD 1 1 Johns Hopkins University School of Medicine 2 Mercer University School of Pharmacy July 27, 2012.

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Jenell Coleman, MD MPH 1 , Ayyappa Chaturvedula PhD 2 , Craig Hendrix, MD 1

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  1. EFFECTS OF HORMONAL CONTRACEPTION ON TENOFOVIR PHARMACOKINETICS:An Exploratory Secondary Data Analysis of MTN-001 Jenell Coleman, MD MPH1, AyyappaChaturvedula PhD2, Craig Hendrix, MD1 1Johns Hopkins University School of Medicine 2Mercer University School of Pharmacy July 27, 2012

  2. HIV PrEPTrials • Possible explanations for divergent trial results • Behavioral: adherence; sexual and partnership characteristics • Sex or hormonal differences Van Damme NEJM 2012; http://www.nih.gov/news/health/sep2011/niaid-28.htm); Thigpen NEJM 2012; BaetenNEJM 2012;Grant NEJM 2010

  3. Tenofovir TDF TFV TFV-DP • Tenofovir disoproxilfumarate (TDF) is administered orally to increase bioavailability of tenofovir (TFV) • Single 300 mg dose • TDF converted to TFV via diester hydrolysis • Absorption: oral bioavailability 25% in fasting state • Distribution: ~7% serum protein bound; Vd 1.3 ± 0.6 L/kg • Metabolism: does not induce or inhibit cytochrome P450 enzymes • Elimination: • Half-life 18 hours (range: 12-19 hours) • Eliminated by glomerular filtration and active tubular secretion • ~80% recovered unchanged in the urine • TFV phosphorylated intracellularly to tenofovir diphosphate (TFV-DP) • Half-life: 150hr (range: 60-175 hr) • Inhibits activity of HIV-1 reverse transcriptase • Incorporates into DNA leading to chain termination

  4. Sex/Hormonal Differences • Gender differences • Small study in HIV-infected participants: Up to1.8-fold higher [TFV-DP] in women vs. men. However, no difference in [TFV] • TFV transporters • Uptake: organic anion transporters (OAT) • Efflux: multi-drug resistant proteins (MRP) CELL Progesterone  OAT-1 MRP-1,-4, -5 hOCT-1 Estrogen OAT-1, -3 hOCT-1 Ljubojevic AJP-Renal Physiol ‘04; PruvostAntimicrob Ag Chemo ‘09; Weilinga J BiolChem ‘03; Hayer-Zillgen Brit J Pharm ‘02; Anderson J. Antimicrob. Chemother. ‘11

  5. Objective & Study Design • Objective: To evaluate the effects of hormonal contraception on tenofovir pharmacokinetics • Design: Exploratory secondary data analysis • MTN-001: Multi-site, randomized study of PK of tenofovir • 138 healthy, HIV negative, sexually active women • Uganda, South Africa, US • Single daily oral dose of TDF • PK sampling at steady-state

  6. Methods • Specimen sampling • US: 6 blood draws over 8 hours • African: 2 blood draws • Contraceptive categories • Non-hormonal: includes intrauterine device, male or female sterilization • Injectable • Oral contraceptive pills • Drug concentrations • Liquid chromatography-tandem mass spectrometry • LLOQ serum 0.3 ng/mL

  7. Methods • #Parameters calculated using superposition principles (Gupta JPKPD 2008). Covariate building conducted by forward addition and backward elimination

  8. Demographics Data are n ( column%) unless specified

  9. Non-Compartmental: US Participants MEDIAN values Non-hormonal n=33 Injectable n=8 Pills n=29

  10. Serum and PBMC PK: US Women, univariate Serum * * PBMC * * *p-value <.02 Mann Whitney Non-hormonal as reference group

  11. Cpredose:ALL Women, univariate PBMC Serum * ** Non-hormonal n=40 Injectable n=59 Pills n=39 *p-value <.000 Mann Whitney **p-value <.006 Non-hormonal as reference group

  12. PK Mixed Effect Modeling • Preliminary and exploratory • 473 concentrations • Statistically significant covariates on PK parameters • Age: CL • Body weight: Vd • Race: CO • Subset of injectable users from the US sites show same trend as NCA analysis • Injectable use not significant in the model Pills Injectable Non-hormonal

  13. PK Mixed Effect Modeling • Empirical Bayesian estimates of CL • 2/8 US subjects with higher clearance Clearance from Injectable group (8 subjects from NCA analysis and 20 from African sites)

  14. Conclusions • PK mixed effect model • Injectable contraception not a statistically significant covariate of TFV CL • In US subset, CL highly influenced by 2 participants - Not statistically significant • Take home message: given the current data, we are unable to determine if hormonal contraception lowers tenofovirconcentrations

  15. Limitations • Secondary data analysis • Study not designed to address this particular question • Did not control for age, which is highly correlated with injectable use • Specific type of oral contraceptive pill (i.e. progestin only or combination) or injectable (i.e. DMPA or “net-en”) unknown • Concentration of effective HIV prevention not known, therefore, even if there is a contraceptive effect, its impact on prevention is unclear

  16. Acknowlegements • MTN-001 Research Participants • MTN-001 Study Team • Clinical Pharmacology Analytical Lab (JHU) • NIH/DIAIDS • FHI360 • SCHARP • CONRAD • Gilead MTN funded by NIAID 5U01AI068633

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