Assessment of Nevirapine Prophylactic and Therapeutic Dosing Regimens for Neonates

Abstract

Background: Nevirapine (NVP) is a key component of antiretroviral prophylaxis and treatment for neonates. We evaluated current World Health Organization (WHO) weight-band NVP prophylactic dosing recommendations and investigated optimal therapeutic NVP dosing for neonates.

Methods: The PHPT-5 study in Thailand assessed the efficacy of "Perinatal Antiretroviral Intensification" to prevent mother-to-child transmission of HIV in women with <8 weeks of antiretroviral treatment before delivery (NCT01511237). Infants received a 2-week course of zidovudine/lamivudine/NVP (NVP syrup/once daily: 2 mg/kg for 7 days; then 4 mg/kg for 7 days). Infant samples were assessed during the first 2 weeks of life. NVP population pharmacokinetics (PK) parameters were estimated using nonlinear mixed-effects models. Simulations were performed to estimate the probability of achieving target NVP trough concentrations for prophylaxis (>0.10 mg/L) and for therapeutic efficacy (>3.0 mg/L) using different infant dosing strategies.

Results: Sixty infants (55% male) were included. At birth, median (range) weight was 2.9 (2.3-3.6) kg. NVP concentrations were best described by a 1-compartment PK model. Infant weight and postnatal age influenced NVP PK parameters. Based on simulations for a 3-kg infant, ≥92% would have an NVP trough >0.1 mg/L after 48 hours through 2 weeks using the PHPT-5 and WHO-dosing regimens. For NVP-based therapy, a 6-mg/kg twice daily dose produced a trough >3.0 mg/L in 87% of infants at 48 hours and 80% at 2 weeks.

Conclusion: WHO weight-band prophylactic guidelines achieved target concentrations. Starting NVP 6 mg/kg twice daily from birth is expected to achieve therapeutic concentrations during the first 2 weeks of life.

Figure 1

Visual predictive check for the NVP population PK model. Lines represent the predicted population 5^th, 50^th and 95^th percentiles and shaded area is the 90% CIs. Observed concentrations from the infants are overlaid (black circles).

Figure 2

Simulated NVP C₂₄ in newborns following (a) 2 mg/kg OD at birth, then 4 mg/kg OD at day 7 to 14 (PHPT-5 dosing) for HIV prophylaxis.; (b) 15 mg once daily from birth until days 14 of life (WHO guidelines); for HIV prophylaxis; (c) 6 mg/kg twice daily and (d) 8 mg/kg twice daily from birth until days 14 of life for HIV treatment. Note: middle line is the 50^th percentile, lower/upper solid lines represent 5^th & 95^th percentiles of simulated data. Trough targets of 0.1 mg/L for prophylaxis and 3.0 mg/L for therapeutic treatment are shown with dotted lines.