Meeting Report 15 th PK Workshop, Washington, 2014 Produced by

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1 Page 1 of 7 HIV Interaction Studies presented at the 15 th International Workshop on Clinical Pharmacology of HIV and HCV Therapy, Washington, April This report summarises interaction studies relating to HIV therapy. Abstracts and presentations are available on (if permission has been given by the authors for them to appear). Contents Interactions with HIV drugs... 2 NVP & Artemether/Lumefantrine (Abstract O_03)... 2 RTV & Erlotinib (Abstract PP_01)... 2 DTG & Supplements (Abstract P_13)... 2 RTV & Dabigatran (Abstract P_14)... 3 Stribild & Comedications (Abstract P_24)... 3 RPV & Food (Abstract P_25)... 3 EFV & Rifapentine/Isoniazid (Abstract P_28)... 4 EFV & Rifampicin (Abstract P_29)... 4 DRV & Cobicistat (Abstract P_49)... 5 TDF & Protease Inhibitors (Abstract P_55)... 5 Interactions between HIV and HCV drugs... 6 ART & Sofosbuvir or Ledipasvir (Abstract O_06)... 6 ART & Boceprevir (Abstract P_18)... 6 ETR & Boceprevir (Abstract P_21)... 7

2 Page 2 of 7 Interactions with HIV drugs NVP & Artemether/Lumefantrine (Abstract O_03) Reduced artemether lumefantrine exposure in HIV infected Nigerian subjects on nevirapine based antiretroviral therapy. Fehintola FA, et al. The effect of NVP on the pharmacokinetics of artemether/lumefantrine (80/480 mg twice daily) was investigated in 11 HIV infected subjects. When compared to data from 16 HIV negative subjects, NVP decreased artemether AUC by 65% and decreased lumefantrine AUC by 60%. No significant change in dihydroartemisinin parameters were noted between groups. The potential for suboptimal antimalarial response due to inadequate artemether/lumefantrine exposure warrants urgent evaluation in malaria infected patients receiving NVP based ART. RTV & Erlotinib (Abstract PP_01) Simulation of the interaction between erlotinib and ritonavir using a physiologically based pharmacokinetic model. Molto J, et al. Erolotinib is mainly metabolized by CYP3A4 but also by CYPs 3A5, 1A1 and 1A2, providing a rationale for drug interactions with antiretroviral drugs. The objective of this study was to simulate the interaction between erlotinib and RTV using a physiologically based pharmacokinetic (PBPK) model. Steady state erlotinib and RTV plasma concentrations were simulated in a virtual population of 50 individuals receiving erlotinib (150 mg once daily) with and without RTV (100 mg once daily) and the effect of a dose reduction of erlotinib in the presence of RTV was also evaluated. The simulated parameters of erlotinib and RTV given separately were in agreement with reference values from literature. Simulated parameters for coadministration indicated increases of 3.01 fold, 2.51 fold and 2.74 fold for erlotinib Ctrough, Cmax and AUC, respectively. A simulated dose reduction of erlotinib to 50 mg once daily with RTV (100 mg once daily) compensated for the increase in erlotinib exposure as erlotinib Ctrough, Cmax and AUC decreased by 3%, 19% and 22%, respectively, relative to erlotinib 150 mg once daily alone. However, these results should be validated in clinical practice. DTG & Supplements (Abstract P_13) The effect of calcium and iron supplements on the pharmacokinetics of dolutegravir in healthy subjects. Song I, et al. The objective of this open label, randomized, 4 period cross over study in healthy adult subjects was to evaluate the effects of calcium and iron supplements on the pharmacokinetics of DTG, both fasted and with food and to determine a dosing strategy when DTG is co administered with these supplements. Subjects (n=12, calcium carbonate; n=11, ferrous fumarate) received a single dose of DTG (50 mg) administered i) alone under fasted conditions; ii) with a single dose of calcium carbonate 1200 mg or ferrous fumarate 324 mg under fasted conditions; iii) with a single dose of calcium carbonate or ferrous fumarate with a moderate fat meal (approximately 30% fat); iv) under fasted conditions 2 hours prior to administration of a single dose of calcium carbonate or ferrous fumarate. When given under fasted conditions, calcium carbonate decreased DTG AUC, Cmax, and C24 by 39%, 37%, and 39%, respectively and ferrous fumarate decreased DTG AUC, Cmax, and C24 by 54%, 57%, and 56%, respectively. Coadministration of DTG with calcium carbonate or ferrous fumarate under fed conditions, or dosing DTG 2 hours prior to the administration of these supplements yielded DTG exposures similar to those when DTG was given alone under fasted conditions. DTG and calcium or iron supplements can be coadministered if taken with a meal. However, under fasted conditions, DTG should be given 2 hours prior or 6 hours after calcium or iron supplements.

3 Page 3 of 7 RTV & Dabigatran (Abstract P_14) Influence of separated and concomitant administration of ritonavir on the anticoagulant effect of dabigatran etexilate in healthy volunteers. Gordon LA, et al. Dabigatran is neither a substrate nor modulator of CYP enzymes, but is a substrate for P gp and may interact with RTV, a P gp inhibitor. This study assessed the effect of concomitant versus separated administration of dabigatran (150 mg single dose) and RTV (100 mg once daily) on thrombin time (TT) in 16 healthy volunteers. P gp inhibition, mediated by RTV, was expected to increase dabigatran area under the effect curve (AUEC) when given concomitantly and this interaction was expected to be circumvented by separating administration. However, a 13% decrease in AUEC was observed when dabigatran was administered 2 h before RTV, and a 6% decrease was observed with simultaneous administration. This decrease was statistically significant during separated, but not concomitant administration. Although statistically significant, the minor decrease observed in AUEC with separated administration would appear to be of limited clinical relevance. Correlation of these results with dabigatran concentrations and the more sensitive clotting assay, ECT, are warranted to confirm these preliminary findings. Stribild & Comedications (Abstract P_24) Co prescription of non HIV medications in HIV infected individuals in five European countries and the possible impact of interactions with Stribild (FTC/TDF/EVG/COBI). Rogatto F, et al. This retrospective study evaluated the co prescription of non HIV medications in 9243 HIV infected individuals on non Stribild containing ART in five European countries (France, Germany, Italy, Spain, and the United Kingdom) and examined the possible interactions with Stribild (FTC/TDF/EVG/COBI). The most common co prescribed medications were identified and ranked. Potential interactions were identified based on the Stribild product label and/or the University of Liverpool HIV DDI database ( druginteractions.org). In total, 255 non ARV medications, including combinations, were identified to be commonly co prescribed and information on the possible interactions was available for 129 drugs. Five drugs (1.96%) were identified that would be contraindicated with Stribild, of which the most commonly co prescribed were salmeterol and simvastatin. Twenty nine (11.39%) of the co medications would require close clinical monitoring with Stribild, with the most frequently co prescribed being alprazolam (1.18%). In these HIV infected patients that were receiving any co medication and not currently treated with Stribild, contraindicated medications were not likely to be prescribed by HIV clinicians (0.71%) and the coprescription of comedications requiring close clinical monitoring was also appreciably low (13.23%). RPV & Food (Abstract P_25) Effect of food on the steady state pharmacokinetics of rilpivirine when administered as a fixeddose combination in HIV 1 infected Ugandan adults. Lamorde M, et al. This study aimed to investigate the effect of food on the steady state pharmacokinetics of RPV when administered as a fixed dose combination tablet containing TDF/FTC/RPV in 15 HIV 1 infected patients using an East African meal. TDF/FTC/RPV was dose in the fasted state, with low fat meal (353 Kcal) and with a moderate fat meal (589 Kcal); both study meals contained a local banana staple (matooke). When compared to administration with a moderate fat meal, fasting decreased RPV AUC and Cmax by 16% and 21%. AUC and Cmax were unchanged during administration with a low fat meal, but Ctrough increased by 15% when compared with the moderate fat meal. RPV exposure was significantly lower when administered in the fasted state, however PK parameters were similar

4 Page 4 of 7 during dosing with either a low fat or moderate fat local meal. These results suggest that the TDF/FTC/RPV fixed dose formulation should be administered with food. EFV & Rifapentine/Isoniazid (Abstract P_28) Efavirenz pharmacokinetics in HIV infected persons receiving rifapentine and isoniazid for TB prevention in ACTG Podanu AT, et al. The effect of rifapentine/isoniazid (rifapentine ~10 mg/kg, isoniazid 300 mg, both once daily) on EFV (600 mg once daily) was evaluated in 87 subjects on a stable EFV containing regimen who enrolled in ACTG Study A5279 (a phase III clinical trial comparing 4 weeks of daily rifapentine/isoniazid to 9 months of daily isoniazid for the prevention of active TB in HIV infected individuals). EFV concentrations were determined pre TB treatment (week 0) and after 2 and 4 weeks of treatment. Pharmacokinetic data were judged acceptable if >80% of participants had EFV concentrations 1 mg/l.median (IQR) EFV concentrations were 2.59 mg/l ( ) at week 0, 2.46 mg/l ( ) at week 2 and 2.54 mg/l ( ) at week 4. The numbers of participants with EFV concentrations 1 mg/l at weeks 0, 2, and 4 were 85 (98%), 81 (93%) and 78 (90%), respectively. Median (IQR) EFV CL/F was 9.3 L/h ( ) at week 0 and 9.8 L/h ( ) with rifapentine/isoniazid. Although the percentage of participants with EFV concentrations 1 mg/l decreased during rifapentine/isoniazid therapy, the proportion did not cross below the pre specified threshold of >80%. These results suggest that that rifapentine/isoniazid for 4 weeks can be co administered with EFV containing ART for the prevention of TB in HIV infected individuals. EFV & Rifampicin (Abstract P_29) The induction effect of rifampicin on efavirenz is time dependent: systematic review of 12 drug interaction studies. Khoo S, et al. EFV induces its own metabolism and 4 16 weeks of treatment are required for it to reach steadystate. Rifampicin is known to lower the plasma concentrations of several antiretrovirals and there have been discordant results from different drug interaction studies of EFV and rifampicin. A systematic review of 12 sequential or cross over studies evaluating EFV and rifampicin was performed and the studies analysed by duration of EFV rifampicin treatment prior to pharmacokinetic evaluation. Results from two longitudinal studies of EFV treated patients with or without TB were used as supportive evidence. Seven studies evaluated <8 days of combined EFVrifampicin treatment, with reductions in EFV Cmin of 19% to 54%, compared with efavirenz alone. Five longer term studies evaluated 4 24 weeks of combined EFV rifampicin treatment, with increases in efavirenz Cmin of 6% to 26%. In two longitudinal studies, differences in EFV Cmin between rifampicin treated and untreated patients were only observed in the first 1 4 weeks of combined treatment, with no significant effects on EFV concentrations during longer term treatment. These results suggest that dose modification of EFV may not be needed during co administration with rifampicin based treatment for TB.

5 Page 5 of 7 DRV & Cobicistat (Abstract P_49) PK and PD of darunavir 800mg qd when coadministered with cobicistat 150mg qd in HIV 1 infected patients with no darunavir RAMs: GS US week 48. Kakuda T, et al. The pharmacokinetics, safety and efficacy of darunavir/cobicistat (800/150mg once daily as singleagents) were evaluated in 313 HIV infected patients with no darunavir resistance associated mutations. Sparse pharmacokinetic samples for darunavir were collected at weeks 2, 4, 8, 12, 16, 24 and 48 in all patients and intense pharmacokinetic sampling for DRV, cobicistat, TDF and FTC was performed in a substudy of 60 subjects. Overall mean (SD) population pharmacokinetic derived darunavir AUC and C0h at week 48 were 102,000 (33,100) ng.h/ml and 2,150 (1,320) ng/ml (n=298), respectively. In the pharmacokinetic substudy, mean (SD) Cmax (ng/ml), C24h (ng/ml) and AUC24h (ng.h/ml) were for darunavir: 7,663 (1,920), 1,310 (969) and 81,646 (26,322); cobicistat: 991 (331), 33 (95) and 7,596 (3,657); tenofovir: 382 (118), 78 (33) and 3,613 (1,203); and emtricitabine: 1,862 (491), 113 (101) and 11,793 (3,490). These pharmacokinetic parameters were comparable to historic data. Once daily darunavir/cobicistat was generally safe and well tolerated; virological and immunological responses were similar to historical data with once daily darunavir/ritonavir. TDF & Protease Inhibitors (Abstract P_55) Should the dose of tenofovir be reduced to mg/day, when combined with protease inhibitors? Hill A, et al. Combining TDF with LPV/r, DRV/r or ATV/r increases tenofovir concentrations, which could raise the risk of renal adverse events. As newly approved tenofovir tablets are available at lower strength (200 or 250 mg) for use in paediatrics, a literature search was performed to assess the effects of LPV/r, DRV/r or ATV/r on TDF Cmax, AUC and Cmin and to determine if use of approved paediatric doses of tenofovir ( mg once daily) could compensate for known drug interactions. In drug drug interaction studies TDF Cmax, AUC and Cmin was significantly increased by LPV/r (15%, 32% and 51%, respectively), ATV/r (34%, 37% and 29%, respectively) and DRV/r (24%, 22% and 37%, respectively) with the effects of each PI on TDF Cmin being greater than effects on Cmax or AUC. Using a 250mg paediatric dose of TDF with LPV/r, TDF Cmin was predicted to remain higher than with TDF 300 mg used with EFV (GMR =1.26, 95% CI ). Similar results were predicted for use of TDF 250 mg with ATV/r (GMR 1.07, 95% CI ) and with DRV/r (GMR 1.14, 95% CI ). TDF AUC levels for the 250 mg dose with PIs were all predicted to be within the bioequivalence range, relative to use with EFV. Using a 200 mg paediatric dose of tenofovir with LPV/r, the TDF Cmin was predicted to be bioequivalent to TDF 300 mg used with EFV (GMR =1.02, 95% CI ). Similar results were predicted for use of TDF 200 mg with ATV/r (GMR 0.86, 95% CI ) and with DRV/r (GMR 0.92, 95% CI ). All three results were within the bioequivalence limits of TDF AUC levels for the 200 mg dose with PIs were predicted to be 8 18% lower than for TDF 300 mg used with EFV. These dose modifications could potentially lower the risk of TDF related renal adverse events, while maintaining consistent levels of efficacy, however, they need to be assessed in prospective pharmacokinetic studies, including analysis of intracellular triphosphate concentrations.

6 Interactions between HIV and HCV drugs Page 6 of 7 ART & Sofosbuvir or Ledipasvir (Abstract O_06) Drug interactions between direct acting anti HCV antivirals sofosbuvir and ledipasvir and HIV antiretrovirals. German P, et al. The interactions between the HCV directly acting antivirals ledipasvir and sofosbuvir and various HIV antiretrovirals were investigated in groups of HIV/HCV negative subjects. Coadministration of ledipasvir (90 mg once daily) and RAL (400 mg twice daily) to 28 subjects had no effect on ledipasvir exposure and only a small (<20%) effect on RAL pharmacokinetics. Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and EFV/FTC/TDF (600/200/300 mg once daily) to 29 subjects had no effect on the pharmacokinetics of sofosbuvir and its main circulating metabolite GS331007, nor on the pharmacokinetics of EFV and FTC. However, ledipasvir exposure decreased by 34% and TDF exposure increased by ~1.8 to 2.6 fold. Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and RPV/FTC/TDF (25/200/300 mg once daily) to 29 subjects had no effect on the pharmacokinetics of ledipasvir, sofosbuvir, GS331007, RPV or FTC, but increased TDF exposure by ~1.3 to 1.9 fold. The increases in TDF exposure were comparable to those achieved when FTC/TDF is administered with ritonavir boosted PIs, which do not warrant dose adjustment. Results from this study and a previous study between sofosbuvir and ARVs demonstrate that ledipasvir/sofosbuvir may be administered with EFV, RPV or RAL, with a backbone of FTC/TDF. ART & Boceprevir (Abstract P_18) Boceprevir and antiretroviral pharmacokinetic interactions in HIV/HCV coinfected persons AIDS clinical trials group study A5309S. Kiser JJ, et al. This study evaluated the pharmacokinetics of boceprevir and ARVs in HIV/HCV infected patients receiving EFV (n=19), RAL (n=17), ATV/r (n=11), DRV/r (n=5) and LPV/r (n=2). Boceprevir had no effect on EFV pharmacokinetics. RAL AUC and Cmax increased by 56% and 87%, respectively, but there was no significant effect on Cmin (10% increase). ATV AUC, Cmin and Cmax decreased by 30%, 43% and 16%, respectively, with the change in Cmax not being significant. DRV AUC, Cmax and Cmin decreased by 42%, 32% and 64%, respectively. When compared to historical data from healthy volunteers, EFV decreased boceprevir AUC, Cmax and Cmin by 11%, 27% and 21%, respectively, whereas ATV/r had no effect on boceprevir pharmacokinetics. In the presence of RAL, boceprevir AUC, Cmax and Cmin increased by 18%, 4% and 8%, respectively. DRV/r increased boceprevir Cmin by 93% but had no significant effect on AUC (3% increase) or Cmax (15% decrease). No statistical tests were performed in the two subjects on LPV/r due to the small sample size, but reductions in both boceprevir and LPV were observed. With the exception of increased RAL exposure, the effects of boceprevir on ARV PK in HIV/HCV co infected patients were similar to those observed in healthy volunteers. A greater decline in boceprevir Cmin with EFV and a reduction in boceprevir exposures with DRV/r were expected, but not observed. The impact of these drug interactions on antiviral safety and efficacy in co infected individuals undergoing HCV treatment is currently being investigated.

7 Page 7 of 7 ETR & Boceprevir (Abstract P_21) Enzyme induction not alterations in protein binding contribute to reduced etravirine exposures with boceprevir. Hammond KP, et al. The aim of this study was to determine if enzyme induction or alterations in protein binding were responsible for the reduction in ETR concentrations when combined with boceprevir. ETR and metabolite concentrations and protein binding were determined in 20 HIV/HCV negative subjects who received boceprevir (800 mg every 8 h) and ETR (200 mg every 12 h) alone and in combination. Four metabolites were detected in human plasma: two di oxygenated (HP M1 and HP M2) and two di alkyl hydroxy (HP M3 and HP M4) products. However, HP M3 was present only in trace amounts and not quantified. HP M2 was predominately produced via the CYP2C19 pathway, while HP M4 was produced by all cytochromes P450 tested with a formation rate trend of CYP2D6 < CYP2B6 < CYP3A5 << CYP2C19 < CYP3A4 ~ CYP2C9. Ratios of ETR parent:metabolite AUCs were higher in the presence of boceprevir, suggesting that boceprevir induces cytochromes P450 in vivo, primarily CYP2C9/19. An increase in the ETR fraction unbound was not observed with boceprevir. Thus, enzyme induction, not an increased fraction of unbound ETR, contributes to the reduced ETR exposures with boceprevir.