CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

Results: RPV CVF and PL samples were collected from 24 US women (12 Black, 11 Hispanic, 1 White). For all samples collected, RPV conc was 70.3 ng/mL (22.9-120.60) in CVF and 92.0 ng/mL (48.9-147.4) in PL, and their ratio was 0.68 (0.28-1.38). Samples were adequate to calculate CVF and PL AUC for 10 2T subjects, 17 3T subjects and 19 PP subjects. CVF and PL conc-time plots and AUCs for each sampling period are presented in the figure. Compared to PP, CVF:PL AUC ratio was lower during 2T (p=.02) and 3T (p=.06). Conclusions: These data demonstrate that with chronic oral RPV dosing, CVF RPV conc is similar to PL, and is likely to achieve inhibitory concentrations. Our data also suggest that CVF conc of RPV may be greater during pregnancy than postpartum.

440 Nevirapine Dosing for Treatment in the First Month of Life Mark Mirochnick 1 ; Karin Nielsen-Saines 2 ; Jose H. Pilotto 3 ; Philippa Musoke 4 ; Avinash Shetty 5 ; Katherine Luzuriaga 6 ; Edmund Capparelli 7 1 Boston Univ Sch of Med, Boston, MA, USA; 2 Univ of California Los Angeles, Los Angeles, CA, USA; 3 Hosp Geral de Nova Iguaçu, Rio de Janeiro, Brazil; 4 Makerere Univ, Kampala, Uganda; 5 Wake Forest Univ, Winston Salem, NC, USA; 6 Univ of Massachusetts Med Sch, Worcester, MA, USA; 7 Univ of California San Diego, San Diego, CA, USA Background: NVP clearance (CL) is low in term neonates and further decreased in preterm infants due to immaturity in CYP2B6 and CYP3A4 activity. NVP autoinduces its own CL but the extent of autoinduction on immature enzyme systems is unknown. While pharmacokinetic (PK) studies have been done to determine NVP dosing regimens for treatment of HIV infection (trough conc target 3.0 ug/mL) in infants after 1 month of life, NVP PK studies under age 1 month are limited to evaluations of dosing regimens for prophylaxis against HIV infection (trough conc target 0.1 ug/mL). Population modeling of these PK data and simulations can be used to evaluate proposed NVP dosing regimens to achieve treatment target conc in term and late preterm infants (34-37 weeks gestation) from birth through 6 months of life. Methods: We developed a NVP population PK model using NONMEM that incorporated data from 192 infants (1121 plasma NVP conc) from US, Africa and Brazil under age 1 yr in 5 PACTG or HPTN protocols. Prematurity effects were estimated from the published literature (de Waal 2014). Dosing regimens from birth through 6 months of age were evaluated using simulations. Simulated NVP doses included 6 mg/kg BID for term infants and 4mg/kg BID for 1 week followed by 6 mg/kg BID for late preterm infants. Proposed PK target was NVP trough conc > 3.0 ug/mL. Results: A one compartment model with first order absorption was used. CL was scaled allometrically and volume of distribution (Vd) was scaled linearly for weight. CL was modeled to mature exponentially with age. Autoinduction of CL was modeled as a linear function of dose. The effects of prematurity and maturation of CYP2B6 and CYP3A4 activity on NVP CL were imputed from published studies. Ttypical CL (L/hr/kg) in term infants increased by nearly 6 fold from birth to 6 months due to maturation and by an additional 79% due to induction. Final simulations used term infant doses of 6 mg/kg BID and late preterm infant doses of 4mg/kg BID for 1 week followed by 6 mg/kg BID. In these simulations, the dosing regimens achieved NVP targ Conclusions: NVP CL is low immediately after birth and increases dramatically over the 1st months of life. Appropriate NVP dosing regimens in neonates must take into account the impact of maturation, auto-induction and prematurity on NVP CL. The dosing regimens supported by these simulations and NVP PK in preterm infants are being studied in the IMPAACT 1115 and 1106 protocols. 441 Prediction of Infant Exposure to Maternal Drugs From Breast Milk Using PBPK Modeling Adeniyi Olagunju 1 ; Rajith Kumar Reddy Rajoli 1 ; Oluseye Bolaji 2 ; David J. Back 1 ; Saye Khoo 1 ; Andrew Owen 1 ; Marco Siccardi 1 1 Univ of Liverpool, Liverpool, UK; 2 Obafemi Awolowo Univ, Ile-Ife, Nigeria Background: Therapeutic drug use during lactation is widespread despite a paucity of data on breast milk excretion and the extent of breastfed infants’ exposure for many drugs. Physiologically-based pharmacokinetic (PBPK) modeling is increasingly used in paediatric studies, with significant regulatory support. Here we present for the first time the development and validation of a PBPK model to predict infant exposure to maternal therapeutic drugs through breast milk. Methods: A bespoke breastfeeding model integrating a whole-body PBPK maternal model with a whole-body PBPK infant model was developed. The model included mathematical descriptions of system and drug-specific parameters regulating absorption, distribution, metabolism and excretion, and breastfeeding. Virtual populations of nursing mothers-infant pairs (n = 100 per infant age group: 10 days-1 month, 1-3 months, 3-6 months, and 6-12 months) were simulated. Simulated mothers received 600 mg efavirenz and infants were exclusively breastfed until 6 months. Suckling rate was assumed to be equal to milk production rate and was kept constant after 6 months to reflect mixed feeding. Pharmacokinetic parameters were obtained at steady state. Model building and simulation was conducted using SimBiology on MATLAB 2014b. Previously published clinical data on efavirenz in a cohort of nursing mother-infant pairs was used for model validation. Results: Key anatomical and physiological parameter predictions were within 50% difference of available clinical data. The model adequately described efavirenz pharmacokinetics, with over 90% of all individual observed data points (n = 29) within the predictive interval. Compared with clinical data, all parameters were within 50% difference. Predicted versus observed breast milk AUC 0-24 , C max and C min were 78.2 (15.3-335) versus 68.5 (26.3-257) µg.hr/mL, 4.65 (1.15-18.0) versus 5.39 (1.43-18.4) µg/mL, and 2.19 (0.283-13.0) versus 1.68 (0.316-9.57) µg/mL, respectively. Model-predicted infant efavirenz dose from breast milk and the resulting plasma concentrations were within 50%

Poster Abstracts

168

CROI 2016