Steady-State Pharmacokinetic Evaluation of Emtricitabine in Neonates Exposed to HIV In Utero

1. Steady-State Pharmacokinetic Evaluation of Emtricitabine in Neonates Exposed to HIV In Utero MR Blum,1 D Ndiweni,2 G Chittick,1 N Adda,1 D Kargl,1 and D Josipovic3 1Gilead Sciences, Inc., Durham, North Carolina, USA; 2Department of Pediatrics, Johannesburg Hospital, Parktown, South Africa; 3Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, Soweto, South Africa

2. Introduction • Emtricitabine (Emtriva®, FTC) is a potent, once daily (QD) nucleoside reverse transcriptase inhibitor approved for the treatment of human immunodeficiency virus (HIV) infection in adults and children ≥ 3 months old in combination with other antiretroviral (ARV) agents • FTC pharmacokinetics (PK) in HIV-exposed infants were examined following short-term multiple-dose administration during the first 3 months of life in order to determine an appropriate dose that would provide a drug exposure similar to those achieved by regimens shown to be safe and efficacious in pediatric patients ≥ 3 months old and adult patients

3. Background • Main elimination route of FTC is via the kidneys into urine, primarily as unchanged drug • Full-term (36 weeks gestation or later) newborn infants have immature kidney function (glomerular filtration rate [GFR] = 40 mL/min/1.73m2) with values similar to adults (GFR = > 90 mL/min/1.73m2) not achieved until > 8 weeks postpartum.1 Therefore, dose adjustment to reflect changing renal function was anticipated in this very young patient 1. Schwartz GJ, Brion LP, Spitzer A. Use of Plasma Creatine Concentration for Estimating Glomerular Filtration Rate in Infants, Children, and Adolescents. Pediatric Nephrology 1987; 34:571-590.

4. Objectives • The primary objectives of the study were to: • evaluate the PK of FTC over the first 3 months of life following multiple‑dose administration in children born to HIV‑1 infected mothers, and • determine how the maturing renal function of neonates < 3 months old affects FTC PK • The secondary objective was to evaluate the safety of FTC when administered to neonates < 3 months old

5. Methods • Two study centers in South Africa enrolled up to 20 HIV-exposed neonates born to women with confirmed HIV‑1 infection • Minimum ARV treatment for the women was IV zidovudine (ZDV) or a single dose of nevirapine during delivery. In practice, women in or close to the last trimester were identified and treated with triple ARV drug therapy • Each child received 6 weeks ZDV for HIV prophylaxis, starting within 24 hours of birth • Infants were enrolled in one of four groups in which two 4-day courses of 3 mg/kg FTC QD, separated by an interval of ≥ 2 weeks, were administered to each infant. The timing of each course was staggered between the groups (see Table 1) in order to assure a continuum of PK assessments over the first 12 weeks of life

6. Methods (cont’d) • 48 hour PK evaluations were conducted following last FTC dose of both FTC courses • Plasma FTC concentrations were measured using validated LC/MS/MS method • PK analysis was conducted using standard non-compartmental methods and parameters were summarized by age on day of PK evaluation (0-21, 22-42, and 43-90 days) • Safety evaluations (physical examination, vital signs and blood for clinical laboratory testing) were performed at birth, at Weeks 2, 6, 12 and 24, and before and after the first and last dose of each FTC course

7. Methods (cont’d) • HIV‑1 DNA and RNA testing was performed at birth and at Weeks 6, 12 and 24. Positive test excluded child from study; however, the child was provided ARV drugs though a post-protocol program. Mothers were also given postpartum access to ARV drugs through the same program • Formula was provided to mothers to minimize postpartum exposure to HIV through breast feeding

8. Schematic of FTC Dosing Schedule X = 3 mg/kg QD dose of FTC administered in AM for each of 4 consecutive days

9. Demographics • All infants were black South Africans; 64% (16/22) were male, and birth weights ranged from 2.0 to 3.8 kg (mean: 2.9 kg)

10. Safety / Disposition • Twenty-two infants were enrolled with 20 completing both FTC courses and PK assessments • One infant received three doses of first course FTC before he was lost to follow-up, and a second infant was discontinued due to anemia (Grade 3) prior to starting his first course of FTC • Bronchopneumonia and gastroenteritis in 1 subject and bronchiolitis in 1 subject, all assessed as unrelated to ZDV or FTC, were the only serious adverse events reported • All 20 infants completing the study were determined to be free of HIV infection at 6 months postpartum

11. Pharmacokinetics • FTC exposure (AUC) in neonates receiving 3 mg/kg FTC QD was in the range of pediatric patients ≥ 3 months old receiving the recommended dose of 6 mg/kg QD and adults receiving 200 mg QD (~10 hr*µg/mL) • FTC AUC decreases with increasing age over the first 3 months of life, which correlates with an increase in total body clearance (CL/F)

12. Mean (%CV) FTC PK Parameters byAge on Day of Assessment a. Mean, range

13. FTC AUC vs. Age in HIV-Exposed Neonates 2 2 5 5 2 2 0 0 AUC = -0.0994 * age + 14.032 R2 = 0.223 1 1 5 5 mL AUC (hr*µg/mL) g/ 1 1 0 0 h C ( U A 5 5 0 0 0 0 2 2 0 0 4 4 0 0 6 6 0 0 8 8 0 0 1 1 0 0 0 0 Age (days)

14. FTC CL/F vs. Age in HIV-Exposed Neonates 9 9 0 0 8 8 0 0 CL/F = 0.3832 * age + 8.1922 R2 = 0.3615 7 7 0 0 6 6 0 0 ) 5 5 0 0 CL/F (mL/min) 4 4 0 0 3 3 0 0 CL/F (mL/min 2 2 0 0 1 1 0 0 0 0 0 0 2 2 0 4 4 0 0 6 6 0 8 8 0 1 1 0 0 0 0 Age (days)

15. Conclusions • A dose of 3 mg/kg FTC QD in neonates < 3 months old produced plasma FTC exposure (AUC) similar to those shown to be safe and efficacious in HIV-infected adults and children ≥ 3 months old • Short (4-day) courses of FTC dosed at 3 mg/kg QD were safe and well tolerated in neonates < 3 months old