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.

Conflict of interest statement

Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to disclose. The study was funded by the National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA. Grants numbers: R01HD052461, R01HD056953.

Figures

Figure 1

Visual predictive check for the NVP population PK model. Lines represent the predicted population 5th, 50th and 95th 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 50th percentile, lower/upper solid lines represent 5th & 95th 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.