EFFECTS OF HORMONAL CONTRACEPTION ON TENOFOVIR PHARMACOKINETICS:

An Exploratory Secondary Data Analysis of MTN-001

Jenell Coleman, MD MPH1, Ayyappa Chaturvedula PhD2, Craig Hendrix, MD1

1Johns Hopkins University School of Medicine2Mercer University School of PharmacyJuly 27, 2012

Study Regimen Relative Risk Reduction (95% CI) Drug Detectible

FEM-PrEP TDF/FTC po qd 0.0 (-0.73 – 0.42) No difference

VOICE TDF po qda 0.0 (-0.35 – 0.35) In Analysis

CDC TDF2 TDF/FTC po qd 0.63 (0.22 – 0.83) In Analysis

PartnersTDF po qd

TDF/FTC po qd

0.67 (0.44 – 0.81)

0.75 (0.55 – 0.87)

0.86 (0.57–0.95) ; BLQ 0.3

0.90 (0.56–0.98) ; BLQ 0.3

iPrEX TDF/FTC po qd 0.42 (0.15 – 0.63) 0.92 (0.40 – 0.99) ; BLQ 10

HIV PrEP Trials

Van Damme NEJM 2012; http://www.nih.gov/news/health/sep2011/niaid-28.htm); Thigpen NEJM 2012; Baeten NEJM 2012;Grant NEJM 2010

•Possible explanations for divergent trial results• Behavioral: adherence; sexual and partnership characteristics• Sex or hormonal differences

Tenofovir

• Tenofovir disoproxil fumarate (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

TFV-DPTFVTDF

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)

Ljubojevic AJP-Renal Physiol ‘04; Pruvost Antimicrob Ag Chemo ‘09; Weilinga J Biol Chem ‘03; Hayer-Zillgen Brit J Pharm ‘02; Anderson J. Antimicrob. Chemother. ‘11

Progesterone OAT-1MRP-1,-4, -5hOCT-1

Estrogen OAT-1, -3hOCT-1

CELL

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

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

MethodsNon-compartmental analysis

PK Mixed Effect Modeling#

N 70 100

Site US alone US and African

Matrix Serum, PBMC Serum

PK parameters DescriptiveCmax, AUC0-8hr,Cpredose

QuantitativeKA, CL, Vc,Vt, CO (parameter to account for predose concentration)

Compartments None 2 with 1st order absorption and lag time

Steady-state assumption

YES NO

Adherence assumption

YES NO

BLQ Imputed as zero Excluded

Variables Contraceptive type Contraceptive type; age; race; body weight; CrCl

Software WinNonLinSTATA

NONMEM

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

DemographicsTOTALN=138

NCAN=70

PK MODELN=100

AGE mean ± SD 31 ± 7 31 ± 8 31 ± 7

RACE

WHITE 33 (23.0) 33 (47.1) 35 (35)

BLACK 93 (67.4) 33 (47.1) 57 (57)

ASIAN 7 (5.1) 2 (2.9) 5 (5)

MULTIRACIAL 5 (3.6) 2 (2.9) 3 (3)

WEIGHT (kg) mean ± SD 77 ± 20 82 ± 21 78 ± 21

CREATININE CLEARANCE mean ± SD 131 ± 37 132 ± 42 131 ± 39

NON-HORMONAL CONTRACEPTION 40 (29) 33 (47.1) 36 (36)

INJECTABLE 59 (42.8) 8 (11.4) 28 (28)

PILLS 39 (28.2) 29 (41.4) 35 (35)

Data are n ( column%) unless specified

Non-Compartmental: US Participants

0tan28a566028 0tan4a566040tan28a566028

0tan19a566019

0tan10a566010

0tan1a56601

0tan21a566021

0tan12a566012

0tan3a56613

0tan23a566123 SERUM [TFV]

NON-HORMONAL PILLS INJECTABLE

HOURS

TFV

(ng/

mL)

0tan28a566028 0tan4a566040tan28a566028

0tan9a56609

0tan19a566019

0tan29a566029

0tan9a56609

0tan19a566019

0tan29a566029PBMC [TFV-DP]

NON-HORMONAL PILLS INJECTABLE

HOURS

TFV-

DP (f

mol

/10^

6 ce

lls)

MEDIAN valuesNon-hormonal n=33Injectable n=8Pills n=29

Serum and PBMC PK: US Women, univariate

*p-value <.02 Mann Whitney Non-hormonal as reference group

*

*

Serum

PBMC

*

*

Cpredose: ALL Women, univariate

*p-value <.000 Mann Whitney**p-value <.006Non-hormonal as reference group

**

*

PBMCSerum

Non-hormonal n=40Injectable n=59Pills n=39

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 Injectable Non-hormonalPills

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)

Conclusions

• PK mixed effect model• Injectable contraception not a statistically significant covariate of TFV CL

• In US subset, CL highly influenced by 2 participants

Take home message: given the current data, we are unable to determine if hormonal contraception lowers tenofovir concentrations

Non-compartmentalAnalysis

Injectable Pills

UNIVARIATE % decrease % decrease

US subgroup

Serum Cpredose - -

Cmax 29 -

AUC 33 -

PBMC Cpredose - -

Cmax - 23

AUC - 27

ALL participants

Serum Cpredose 57 -

PBMC Cpredose 73 -

- Not statistically significant

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

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