Nevirapine (NVP) clearance is low immediately after birth and increases dramatically over the first months of life. Population modelling and pharmacokinetic (PK) simulations shown at CROI 2016 predicted dosing regimens to achieve target NVP treatment concentrations in term and late preterm infants.

NVP clearance is low in term neonates, and lower still in preterm ones, because of immaturity in CYP2B6 and CYP3A4 activity. Clearance is also autoinduced in proportion to the size of the NVP dose in the first years of life.

PK data are available to guide NVP dosing for treatment of HIV in infants after one month of life: trough concentration target 3.0 ug/mL. But NVP PK studies in infants less than one month old are limited to evaluations of dosing regimens for prevention of vertical transmission: trough concentration target 0.1 ug/mL.

Increasing evidence for early treatment and trends on early infant diagnosis -- as well as a paucity of other antiretroviral options in this age group -- has led to considerable interest in the use of NVP as part of ART regimens for neonates.

Mark Mirochnick and colleagues from the IMPAACT network presented findings from a study that used population modelling to evaluate proposed NVP dosing regimens to meet target concentrations in term and late preterm infants (34-37 weeks gestation) from birth to 6 months old.

The investigators developed a NVP population PK model using NONMEM. The model included data from 192 infants (1121 plasma NVP concentrations) from US, Africa and Brazil in five PACTG or HPTN studies.

CYP286 metaboliser status, rate of autoinduction, and preterm effects were estimated from published literature. Dosing regimens from birth through 6 months of age were evaluated using simulations. Simulations were used to evaluate proposed NVP doses of 6 mg/kg twice daily for term infants and 4mg/kg twice daily for one week followed by 6 mg/kg twice daily for late preterm infants. The target was to meet trough concentrations of > 3.0 ug/mL.

The investigators used a one-compartment model with first order absorption. Clearance was scaled allometrically and volume of distribution scaled linearly for weight. It was modelled to mature with age and autoinduction as a linear function of dose. The investigators inputed effects of prematurity and maturation of CYP2B6 and CYP3A4 activity on NVP clearance from published data.

They noted that typical NVP clearance (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. The final simulations used term infant doses of 6 mg/kg twice daily and late preterm infant doses of 4mg/kg twice daily for one week followed by 6 mg/kg twice daily. In these simulations, the dosing regimens achieved NVP targets.

The investigators concluded that NVP dosing regimens in neonates must take into account the impact of maturation, auto-induction and prematurity on NVP clearance.

Comment

There is increasing interest in using ART regimens early in life in HIV infected neonates and those at high risk of infection. NVP is one of the few antiretrovirals with some PK and safety data in this age group and formulations for neonates. The dosing regimens in these simulations and NVP PK in preterm infants are being evaluated in the IMPAACT 1115 and 1106 trials.

Table 1 shows the lack of antiretroviral options for neonates and includes ongoing and planned IMPAACT trials that will provide some data to guide dosing. Without better data and formulations it is unclear how very early treatment of neonates will be achieved.

Table 1: Antiretrovirals Available for Neonates (Including Ongoing and Planned IMPAACT Trials)
DrugPretermTerm2 weeks
Nucleos(t)ide Reverse Transcriptase Inhibitors
ABCP1106 < 2500 g  
AZT
ddI  
d4TP1106 < 2500 g
FTC 
TAFP1026s washoutP1026s washout 
3TCP1106 < 2500 g
Non-nucleoside Reverse Transcriptase Inhibitors
DoravirineP1026s washoutP1026s washout 
EFVP1026s washoutP1026s washout 
ETRP1026s washoutP1026s washout 
NVPP1106 < 2500 gP1115 >34 weeks GA
RPV   
Protease Inhibitors
ATV   
DRVP1026s washoutP1026s washout 
LPVP1026s washout
P1106 <2500 g
P1026s washout
Integrase Inhibitors
DTGP1026s washoutP1026s washout
P1093 dosing (in development)
P1093 dosing (in development)
EVGP1026s washoutP1026s washout 
RALP1097 washoutP1097 washout
P1110 dosing
 
CCR5 Receptor Antagonist
Maraviroc In development 

Adapted from Ruel T. IMPAACT 2015.

Reference

Mirochnick M et al. Nevirapine dosing for treatment in the first month of life. Conference on Retroviruses and Opportunistic Infections. 22-26 February 2016. Boston. Poster abstract 440.
www.croiconference.org/sessions/nevirapine-dosing-treatment-first-month-life-0 (Abstract)
www.croiconference.org/sites/default/files/posters-2016/440_0.pdf (Poster)
www.croiwebcasts.org/console/player/29499?mediaType=slideVideo& (Themed discussion)