CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

456

Multiple-Dose Treatment With Rifabutin Reduces the Exposure of Doravirine Sauzanne Khalilieh 1 ; KellyYee 1 ; Rosa Sanchez 1 ; Rachael Liu 1 ; Li Fan 1 ; Maureen Martell 2 ; Radu Pop 2 ; Heather Jordan 3 ; Marian Iwamoto 1 1 Merck & Co, Inc, Kenilworth, NJ, USA; 2 Pharma Medica Rsr, Inc, Mississauga, ON, Canada; 3 Pharma Medica Rsr, Inc, St. Charles, MO, USA

Background: Doravirine is a novel, potent, HIV-1 non-nucleoside reverse transcriptase inhibitor that is primarily metabolized by oxidation via CYP3A4. A previous clinical trial demonstrated that co-administration of doravirine with multiple dose (MD) rifampin, a strong CYP3A4 inducer, resulted in decreased doravirine exposure. This study assessed the impact of MD rifabutin administration, a moderate CYP3A4 inducer, on the pharmacokinetics (PK) of doravirine. Methods: This was an open-label, 2-period, fixed-sequence study in healthy adult subjects. In Period 1 (P1), a single dose (SD) of 100 mg doravirine was administered on Day 1. In Period 2 (P2), following a 7-day washout, rifabutin 300 mg was administered once daily for 16 days and co-administered with 100 mg doravirine on Day 14. Blood samples to measure doravirine concentrations were collected through 72 hours post-dose in P1 and P2. Results: Eighteen subjects (15 male and 3 female) were enrolled. Following co administration with MD rifabutin, doravirine Cmax was not affected; however, exposure and C24 values were reduced. The geometric mean ratios (90% confidence intervals) [doravirine +MD rifabutin/doravirine] for Cmax, AUC0-∞, and C24hr were 0.99 (0.85, 1.15), 0.50 (0.45, 0.55), and 0.32 (0.28, 035), respectively. There were no serious adverse experiences (AEs) and most AEs were mild in intensity. Three (16.7%) and 16 (94.1%) subjects reported at least 1 AE in P1 and P2, respectively. Most AEs in P2 were related to rifabutin treatment. The most common AEs were headache (1 subject in P1 and 8 subjects in P2) and fever (7 subjects in P2). Six subjects discontinued (DC’d) the study due to AEs: in P1, 1 subject was DC’d due to elevated GGT; in P2, prior to receiving doravirine, 5 subjects were DC’d due to fever with or without other flu-like signs and symptoms. Conclusions: Doravirine was generally well tolerated when administered alone or with rifabutin. Multiple dosing of rifabutin significantly reduced doravirine AUC0-∞ and C24 via CYP3A4 induction. However, increasing the dose of doravirine above the clinical dose of 100 mg may mitigate the interaction such that rifabutin, and other moderate CYP3A4 inducers, may be co-administered with doravirine. 457 Pharmacokinetics of Anti-TB Drugs in HIV-Infected and -Uninfected ChildrenWith TB Agibothu KupparamHemanth Kumar 1 ; Geetha Ramachandran 1 ;T. Kannan 1 ; P.K. Bhavani 1 ; S. Ramesh Kumar 1 ; N. Ravichandran 2 ; S. Kalpana 3 ; G. N. Sanjeeva 4 ; Dipti Agarwal 5 ; Soumya Swaminathan 1 1 Natl Inst for Rsr in Tuberculosis, Chennai, India; 2 Government Hosp of Thoracic Med, Chennai, India; 3 Inst of Child Hlth, Chennai, India; 4 Indira Gandhi Inst of Child Hlth, Bengaluru, India; 5 Sarojini Naidu Med Coll, Agra, India Background: The diagnosis and treatment of children with tuberculosis (TB) is increasingly becoming a priority for national TB control programmes. Not many studies have investigated the impact of HIV infection on anti-TB drug concentrations in children. This study compares the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) and nutritional status between HIV-infected and uninfected children with TB and correlate drug pharmacokinetics with TB treatment outcomes. Methods: HIV-uninfected (n=84) and HIV-infected (n=77) children with TB receiving standard thrice weekly treatment, were recruited from six hospitals in India. All consecutive children attending the TB clinics of these hospitals during 2010 - 2013, meeting the study criteria and willing to participate in the study were recruited. Children had received anti-TB treatment (ATT) according to the Indian National Program guidelines for at least two weeks. Semi-intensive pharmacokinetic sampling was performed during intensive phase of ATT after directly observed administration of drugs. Drug concentrations were measured by high performance liquid chromatography. INH aceylator status was determined using saliva. Nutritional assessment was done by computing z scores based on the child’s height, weight, age and gender. Children were followed up and treatment outcomes noted. Results: Children with HIV & TB had significantly lower RMP peak concentration (Cmax) (2.6 vs. 5.1 ug/ml; p<0.001) and exposure (AUC 0-8) (10.4 vs. 23.4 ug/ml.h; p <0.001) than those with TB. Among HIV-infected children, a significantly higher proportion had stunting (77% vs 29%; p<0.001) and underweight (73% vs 38%; p<0.001) compared to children with TB. Combining both groups, RMP Cmax (p=0.001; AOR=1.437; 95% CI:1.157 - 1.784) and PZA Cmax (p=0.027; AOR = 1.041; 95% CI: 1.005 - 1.079) significantly influenced treatment outcome. Conclusions: HIV infection was associated with lower Cmax of RMP and INH and AUC 0-8 of RMP. Ov er 90 % of children in both groups had sub-theapeutic RMP Cmax. Cmax of RMP and PZA significantly influenced TB treatment outcome in children with TB. This study, for the first time, has compared pharmacokinetic and nutritional data between HIV infected and uninfected children with TB. The findings have important clinical implications and suggest the need to increase anti-TB drug doses in children with HIV & TB. 458 Optimal Use of Efavirenz in HIV+/ TB+ Coinfected Children Aged 3 to 24 months Carolyn Moore 1 ; Pearl Samson 2 ; Edmund Capparelli 3 ; Mutsawashe Bwakura-Dangarembizi 4 ; Patrick Jean-Philippe 5 ; Nahida Chakhtoura 6 ; Alex Benns 7 ; Bonnie Zimmer 7 ; Chivon McMullen-Jackson 8 ; Ellen G. Chadwick 9 1 Cntr for Infectious Disease Rsr in Zambia, Lusaka, Zambia; 2 Harvard Sch of PH, Boston, MA, USA; 3 Univ of California San Diego, San Diego, CA, USA; 4 Univ of Zimbabwe, Harare, Zimbabwe; 5 Henry M. Jackson Fndn for the Advancement of Military Med, Inc, Rockville, MD, USA; 6 Eunice Kennedy Shriver NICHD, Bethesda, MD, USA; 7 Frontier Sci & Tech Rsr Fndn, Inc, Amherst, MA, USA; 8 Baylor Coll of Med, Houston, TX, USA; 9 Northwestern Univ, Chicago, IL, USA Background: Poor tolerability and interactions between ARVs and rifampin-containing anti-TB therapy (ATT) limit treatment options for HIV+/TB+ children. EFV has minimal interactions with rifampin, making it a good option for HIV/TB co-infection but PK variability and formulation issues have precluded dosing guidelines for young children. We

Poster Abstracts

176

CROI 2016