CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

representing molecular, physiological and anatomical processes defining PK. PIO, REP and EFV plasma profiles were simulated in 50 virtual individuals receiving either PIO 15 mg once daily (QD) or REP 2 mg thrice daily (TID) with or without EFV 600 mg QD for 14 days. Dose adjustments of PIO and REP were simulated to overcome the DDI with EFV. Results: Simulated PK parameters were in agreement with observed clinical data. Simulated versus observed mean AUC and Cmax ( ± SD) were: 3699 (1413) vs 5020 (1070) ng.h/ ml and 535 (80) vs 597 (115) ng/ml for PIO; 50 (16) vs 69 (78) ng.h/ml and 21 (5) vs 48 (32) ng/ml for REP; 92931 (44533) vs 58089 (23046) ng.h/ml and 6158 (1855) vs 4072 (1168) ng/ml for EFV. The geometric mean ratios with 90% confidence interval (GMR, 90% CI) of PIO or REP with and without EFV are presented in the table. An increase in PIO and REP dosage to 22.5 mg QD and 4 mg TID, respectively, was predicted to be sufficient to overcome EFV induction.

Conclusions: The prediction of DDI for drugs whose metabolism is concurrently induced and inhibited can be complex. The developed model, integrating both concurrent effects on CYPs and temporal changes in drug concentrations, shows that EFV has mainly an inducing effect on PIO and REP metabolism. PBPK modeling represents a useful tool to predict complex DDI as often encountered in multimorbid elderly HIV-infected patients and to support the design of prospective clinical trials.

532 In Silico Simulation of Interaction Between Rifampicin and Boosted Darunavir Marco Siccardi ; Owain Roberts; Rajith Rajoli; Laura Dickinson; Saye Khoo; Andrew Owen; David Back University of Liverpool, Liverpool, United Kingdom

Background: The optimization of antiretroviral regimens in HIV-infected patients co-administered with anti-TB drugs is challenging since rifampicin (RIF), a principal element of the anti-TB therapy, is a strong inducer of key metabolic enzymes. Physiologically-based pharmacokinetic (PBPK) modelling represents an innovative approach to simulate clinical scenarios in the absence of clinical data, by integrating in vitro data in mathematical models. The aim of this research was to develop a PBPK model for the co-administration of ritonavir-boosted darunavir (DRV/r) and RIF and predict optimal dosing strategies to overcome the drug-drug interaction (DDI). Methods: In vitro data describing physicochemical properties, absorption, distribution, metabolism and elimination (ADME) of DRV, ritonavir (RTV) and RIF, as well as the inhibition and induction potential of RTV and RIF were determined experimentally or obtained from the literature. A PBPK model was developed integrating experimental in vitro data in algorithms representing molecular, physiological and anatomical processes defining ADME. The PK of DRV/r and RIF was simulated in 100 virtual individuals. The impact of RIF (600mg qd ) on DRV/r was determined and DRV and RTV qd and bid dose adjustments were simulated. Results: Simulated DRV/r pharmacokinetic parameters were (mean ± SD) C trough (2.02 ± 1.17 μ g/ml), C max (8.23 ± 1.73 μ g/ml) and AUC (115.6 ± 32.9 μ g/mL.h), which is in agreement with observed PK data for DRV/r 800/100 mg qd in HIV-infected patients: C trough (2.11 ± 1.22 m g/ml), C max (6.75 ± 1.68 μ g/ml) and AUC (75.62 ± 26.44 μ g/mL.h). The simulated effect of RIF on DRV exposure resulted in a decrement of 57.7% for AUC, 79.5% for C trough and 34.6% for C max . The effect of RIF was overcome by increasing the DRV/ r dose to 1600/200 mg qd or 800/100 mg bid (Table 1).

Oral Abstracts

Conclusions: The developed PBPK model predicted the in vivo pharmacokinetics of DRV/r and the interaction with RIF. Based on these findings, a DRV/r regimen of 1600/200 mg qd or 800/100 mg bid could mitigate the effect of RIF on DRV/r PK. Mechanistic evaluation of ADME can inform PBPK models and prediction of interaction between drugs. PBPK may be particularly helpful for the rational design of clinical trials evaluating dose adjustment strategies to overcome DDIs in patients concomitantly receiving antiretrovirals and anti-TB drugs. 533 Pharmacogenetics of Pregnancy-Induced Changes in Efavirenz Pharmacokinetics Adeniyi Olagunju 1 ; Oluseye Bolaji 2 ; Alieu Amara 1 ; Laura Else 1 ; Ogechi Okafor 3 ; Ebunoluwa Adejuyigbe 2 ; Oyigboja Johnson 4 ; David Back 1 ; Saye Khoo 1 ; Andrew Owen 1 1 University of Liverpool, Liverpool, United Kingdom; 2 Obafemi Awolowo University, Ile-Ife, Nigeria; 3 Bishop Murray Medical Centre, Makurdi, Nigeria; 4 Catholic Caritas Foundation of Nigeria, Makurdi, Nigeria Background: Physiological changes during pregnancy coupled with single nucleotide polymorphisms (SNPs) in drug disposition genes are known to alter the pharmacokinetics (PK) of many drugs. In the present study the magnitude of pregnancy-induced changes in efavirenz (EFV) PK in genetically-defined subgroups was investigated. Methods: This was an observational study with an enrichment design conducted in two phases. In the preliminary phase, we explored associations between selected CYP2B6 , NR1I3 , CYP2A6 , and ABCB1 SNPs and mid-dose EFV concentrations in an unselected cohort of HIV positive women during pregnancy and postpartum. In the second phase, patients were stratified according to CYP2B6 516G>T (rs3745274). Accordingly, randomly selected patients in each genotype group were invited for the intensive PK phase; samples were collected at 0.5, 1, 2, 4, 8, 12 and 24 hours after an observed evening dose of EFV. Results: A total of 211 HIV positive women taking EFV-based regimens for prevention of mother-to-child transmission (PMTCT) of HIV during pregnancy (n = 77) or postpartum (n = 134) were recruited. Of the nine SNPs investigated, only CYP2B6 516G>T was independently associated with EFV plasma concentrations during both pregnancy and postpartum and was used to pre-select patients for the intensive PK phase. A global comparison showed a 42.6% increase in CL/F (p = 0.02), 29.8% reduction in AUC 0-24 ( p = 0.02) and 50.7% reduction in C min ( p = 0.01) during pregnancy compared with postpartum. The median (range) C min was 1000 ng/ml (429-5190) and the change in C max was not statistically significant ( p = 0.07). However, when stratified for CYP2B6 516G>T status, EFV CL/F increased by 100% during pregnancy compared with postpartum ( p = 0.001) in patients with

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CROI 2015