Effects of Gender, Race, Age & BMI on the Pharmacokinetics of Long-Acting Rilpivirine (RPV-LA) after a Single IM Injection in HIV negative subjects.

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1 Effects of Gender, Race, Age & BMI on the Pharmacokinetics of Long-Acting Rilpivirine (RPV-LA) after a Single IM Injection in HIV negative subjects. Laura Else 1, Akil Jackson 2, Deidre Egan 1, Zeenat Karolia 2, David Back 1, Saye Khoo 1, Natalia Seymour 2, Brian Gazzard 2, Marta Boffito 2 1 Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK 2 St. Stephen s AIDS Trust, Chelsea & Westminster Hospital, London, UK

2 Background: PrEP Trials Trial Population Agent TDF2 1 Heterosexual (46% female) high prevalence area TDF/FTC p.o. daily iprex 2 CAPRISA Partners PrEP 4 FEM PrEP 5 VOICE 6 MSM/transgender women high risk population Heterosexual females high risk area Heterosexual (38% female) Discordant couples Heterosexual females high risk population Heterosexual females high prevalence area TDF/FTC p.o. daily TDF 1% gel coital TDF/FTC or TDF alone p.o. daily TDF/FTC p.o. daily TDF 1% gel daily TDF/FTC or TDF alone p.o. daily 1 Thigpen et al,n Engl J Med 367,5; 2 Grant et al;,n Engl J med 2010,363; 3 Karim et al,science 2010,329; 4 6 th Baeten et al, N Engl J Med,367, 5; 5 van Damme et al, N Engl J Med, 367,5; 6 Marrazzo J, et al. 20 th CROI. Atlanta, Abstract 26LB.

3 % detectable drug % efficacy Background: OVERALL MALES FEMALES FEMALES TOPICAL TDF21 PARTNERS2 IPREX 3 FEMPREP 4 CAPRISA 5 VOICE 6 Risk of HIV acquisition with PrEP - detectable drug - adherence (risk perception) - HIV incidence rates PrEP trials indicate gender-related differences in % efficacy, adherence and detectable drug concentrations Young women are more vulnerable 4,6 - adherence to daily regimens Products that are long acting and require minimal daily adherence may be more suitable for this population." 0 HIV+ HIV- HIV+ HIV- HIV+ HIV- HIV+ HIV- HIV+ HIV- All TDF2 PARTNERS IPREX FEMPREP4 CAPRISA VOICE 1 Thigpen et al N Engl J Med 367;5 Suppl; 2 Donnell et al, CROI 2012; Abstract 30; 3 Grant et al;,n Engl J med 2010,363; 4 van Damme et al, N Engl J Med, 367,5; 5 Kashuba et al XVIII AIDS Conference 2010; 6 Marrazzo J, et al, 20th CROI; Abstract 26LB

4 % detectable drug % efficacy Background: OVERALL MALES FEMALES FEMALES TOPICAL TDF21 PARTNERS2 IPREX 3 FEMPREP 4 CAPRISA 5 VOICE 6 Risk of HIV acquisition with PrEP - detectable drug - adherence (risk perception) - HIV incidence rates PrEP trials indicate gender-related differences in % efficacy, adherence and detectable drug concentrations Young women are more vulnerable 4,6 - adherence to daily regimens Products that are long acting and require minimal daily adherence may be more suitable for this population." 0 HIV+ HIV- HIV+ HIV- HIV+ HIV- HIV+ HIV- HIV+ HIV- All TDF2 PARTNERS IPREX FEMPREP4 CAPRISA VOICE 1 Thigpen et al N Engl J Med 367;5 Suppl; 2 Donnell et al, CROI 2012; Abstract 30; 3 Grant et al;,n Engl J med 2010,363; 4 van Damme et al, N Engl J Med, 367,5; 5 Kashuba et al XVIII AIDS Conference 2010; 6 Marrazzo J, et al, 20th CROI; Abstract 26LB

5 Objectives: Provide an overview of RPV-LA pharmacokinetics after administration of a single IM dose of 300, 600 & 1200 mg in healthy male (n=6) and female (n=60) subjects (SSAT040) To determine the effects of subject demographics (gender, race, age, bodyweight, BMI, RPV concentrations) on the pharmacokinetics of RPV-LA in: - plasma (males and females; n=66) - female genital tract (cervicovaginal fluid and vaginal tissue; n=60)

6 Methods: SSAT040 study population & design Prospective, open-label, stratified-dose exploratory study investigating RPV-LA PK in HIV negative volunteers (60 female, 6 male) - Female: > 50% of enrolled; self-identified African or African-Caribbean ancestry Females (n=20; per arm): administered 300, 600 & 1200 mg IM RPV-LA single dose Males (n=6): administered 600 mg IM RPV-LA single dose PK sampling performed over day 0-84 post-dose, in the following matrices: - plasma - cervicovaginal fluid (CVF; females) - rectal fluid (RF; males) Tissue biopsies taken at two timepoints (either day 7, 14, 28 or 56) - Vaginal tissue (VT; females) - Rectal tissue (RT; males)

7 Methods: Bio-analysis Total ion count RPV concentrations in all matrices were quantified using HPLC-MS/MS Matrix LLQ %Rec Extraction Plasma 0.75 ng/ml 104 Protein precipitation CVF 0.75 ng/ml 78 Protein precipitation Rilpivirine RF (swabs) ng/sample 104 Liquid-liquid Tissue ng/sample 100 Protein precipitation Z-isomer Deuterated internal standard (d4-rpv) used d4-rilpivirine Separation of the active E (RPV) and inactive Z isomers Short and long-term stability (+ photosensitivity) studies conducted

8 Methods: Statistical analysis Pharmacokinetic parameters (AUC 84, C max, C 28, 56, 84 ) calculated by noncompartmental analysis (WinNonlin) PK parameters log transformed and dose normalised (to 300mg) Analysis of covariates gender, weight, BMI, age & ethnicity on systemic (plasma) and compartmentalised (female genital tract) PK performed using univariate and multivariate regression (backwards elimination; SPSS)

9 Results: SSAT040 demographics RPV 600 mg Females (n=60) Males (n=6) median range median range P value Age (yr) wt. (kg) BMI (kg/m 2 ) ethnicity Black African/Caribbean Caucasian Asian Other Values are given as median (range) with non-parametric P-values (Mann Witney test) when comparing continuous variables and P-values (Chi-square or Fisher s exact tests) when comparing categorical variables

10 Plasma (female) 300, 600 & 1200 mg doses: Dose proportionality: geometric mean (90% CI) 160,00 140,00 120,00 PK parameter F 300 mg (n=20) F 600 mg (n=20) F 1200 mg (n=20) C max ng/ml 33.7 ( ) 81.9 ( ) ( ) T max day 7.9 ( ) 6.0 ( ) 6.2 ( ) C 28 ng/ml 19.3 ( ) 44.2 ( ) 82.9 ( ) C 56 ng/ml 9.1 ( ) 22.6 ( ) 45.3 ( ) C 84 ng/ml 6.4 ( ) 16.2 ( ) 30.2 ( ) AUC 84 ng.day/ml ( ) 2934 ( ) ( ) RPV (ng/ml) 100,00 80,00 60,00 40,00 20,00 0, Time (days)

11 Plasma 600 mg doses: Males vs. females: geometric mean (90% CI) 160,00 140,00 120,00 PK parameter M 600 mg (n=6) F 600 mg (n=20) % Difference C max ng/ml 114 ( ) 81.9 ( ) 39% (P=0.057) T max day 5.0 ( ) 6.0 ( ) 17% C 28 ng/ml 58.9 ( ) 44.2 ( ) 33% C 56 ng/ml 27.4 ( ) 22.6 ( ) 21% C 84 ng/ml 15.9 ( ) 16.2 ( ) AUC 84 ng.day/ml 3873 ( ) 2934 ( ) 32% (P=0.065) RPV (ng/ml) 100,00 80,00 60,00 40,00 20,00 0, Time (days)

12 CVF 300, 600 & 1200 mg doses: Dose proportionality: geometric mean (90% CI) 180,00 160,00 140,00 120,00 PK parameter F 300 mg (n=20) F 600 mg (n=20) F 1200 mg (n=20) C max ng/ml 67.4 ( ) 99.3 ( ) ( ) T max day 5.3 ( ) 7.2 ( ) 8.5 ( ) C 28 ng/ml 24.8 ( ) 39.4 ( ) 84.8 ( ) C 56 ng/ml 12.4 ( ) 18.3 ( ) 35.9 ( ) C 84 ng/ml 11.7 ( ) 14.9 ( ) 35.9 ( ) AUC 84 ng.day/ml ( ) ( ) ( ) RPV (ng/ml) 100,00 80,00 60,00 40,00 20,00 0, Time (days)

13 CVF & RF 600 mg doses: Males (rectal) and females (CVF): geometric mean (90% CI) 180,00 160,00 140,00 120,00 PK parameter M 600 mg (n=6) F 600 mg (n=20) % Difference C max ng/ml 35.6 ( ) 99.3 ( ) 64% T max day 6.2 ( ) 7.2 ( ) 13% C 28 ng/ml 11.9 ( ) 39.4 ( ) 70% C 56 ng/ml 5.9 ( ) 18.3 ( ) 68% C 84 ng/ml 1.6 ( ) 14.9 ( ) 89% AUC 84 ng.day/ml 935 ( ) ( ) 70% RPV (ng/ml) 100,00 80,00 60,00 40,00 20,00 0, Time (days)

14 VT & RT 600 mg doses: Males (RT) and females (VT): geometric mean (90% CI) [RPV] in VT/RT F 600 mg M (RT) 600 mg % difference Day 7 ng/ml (n=5) 39.4 ( ) 93.6 ( ) 137% Day 14 ng/ml (n=10) 41.4 ( ) 70.2 ( ) 69% Day 28 ng/ml (n=15) 33.8 ( ) Day 56 ng/ml (n=10) 500,00 RPV (ng/ml) 50,00 5, Time (days)

15 Predictors of plasma RPV C max Univariate and multivariate analysis C max (n=66) Factor Estimated coefficient Univariate models Final multivariate model %effect P value Estimated coefficient %effect Incorporation into full multivariate model based on P<0.1 Final multivariate model based on backwards elimination (P<0.1) P value Gender, female vs. male Weight, kg BMI, kg/m Age, years Race, Black vs. Caucasian

16 Predictors of plasma RPV AUC 84d Univariate and multivariate analysis AUC 84d (n=66) Factor Estimated coefficient Univariate models Final multivariate model %effect P value Estimated coefficient %effect Incorporation into full multivariate model based on P<0.1 Final multivariate model based on backwards elimination (P<0.1) P value Gender, female vs. male Weight, kg BMI, kg/m Age, years Race, Black vs. Caucasian

17 Results: Statistical analysis (systemic; males and females; n=66) There was a significant effect of gender and BMI on RPV plasma C max - female sex and high BMI = RPV C max Gender (but not BMI) was associated with overall RPV exposure (AUC 84d ) No effect of gender and BMI with RPV [plasma] at day 28, 56 & 84 - influence on absorption? No effect of age, bodyweight or ethnicity on RPV [plasma] PK

18 Results: Correlation between [RPV] in plasma with CVF & VT; stratified by dose n = 520 paired samples (r 2 =0.518; P<0.01) n = 100 paired samples (r 2 =0.139; P<0.01) 300 mg: r 2 =0.559;P<0.01; n= mg: r 2 =0.363;P<0.01; n= mg: r 2 =0.449;P<0.01; n= mg: not significant; n= mg: not significant; n= mg: not significant; n=36

19 Predictors of CVF RPV AUC 84d Univariate and multivariate analysis CVF AUC 84d (n=60) Factor Estimated coefficient Univariate models Final multivariate model %effect P value Estimated coefficient %effect Incorporation into full multivariate model based on P<0.1 Final multivariate model based on backwards elimination (P<0.1) P value Plasma AUC, ng.day/ml Weight, kg BMI, 25 vs. <25 kg/m Age, <40 years vs. 40 years Race, Black vs. Caucasian

20 Predictors of VT RPV (day 14) Univariate and multivariate analysis n = 86 paired samples (r 2 =0.107; P=0.002) VT day 14 (n=31) Factor Estimated coefficient Univariate models Final multivariate model %effect P value Estimated coefficient %effect Incorporation into full multivariate model based on P<0.1 Final multivariate model based on backwards elimination (P<0.1) P value CVF AUC, ng.day/ml < Weight, kg BMI, 25 vs. <25 kg/m < <0.001 Age, <40 years vs. 40 years Race, Black vs. Caucasian

21 Results: Statistical Analysis (compartmental; female genital tract) Age (< 40 years) & BMI (>25 kg/m 2 ) were associated with lower RPV AUC 84 & C max in CVF - independent of RPV [plasma] - Effects of age & BMI on [CVF] lost at day 28, 56 & 84 [CVF] & BMI were predictors of RPV concentrations in vaginal tissue [VT] - effects of BMI on [VT] lost at 28 days post-dose

22 Conclusions (1): Post-hoc analyses indicate that BMI and gender may impact on absorption (C max ) of parenteral RPV-LA Effect of gender potentially due to differences in adipose tissue distribution In the female genital tract: changes in ph, stage of menstrual cycle, level of mucus production and permeability of vaginal epithelium can also impact on RPV-LA distribution

23 Conclusions (2): These preliminary findings are limited by: - small number of males in SSAT040 - lack of comparative rectal fluid concentrations in females MWRI_01 study (currently recruiting): to determine RPV-LA PK following single and multiple dosing in HIV negative males (n=6 per arm) and females (n=12 per arm) in: -plasma - vaginal fluid and tissue - endocervical fluid and tissue - rectal fluid and tissue (males and females)

24 Acknowledgements: SSAT - volunteers - research team University of Liverpool - Deirdre Egan Tibotec/Janssen -Peter Williams -Rene Verloes - Jens van Roey Bill & Melinda Gates Foundation -Stephen Becker -Joe Romano -Kim Shaffer