Pharmacokinetics of currently available antiretroviral options for young children

1 April 2013. Related: Conference reports, Antiretrovirals, Paediatric care, PK and drug interactions, CROI 20 (Retrovirus) 2013.

Polly Clayden, HIV i-Base

While we wait for the lopinavir/ritonavir (LPV/r) sprinkles for young children, two posters at CROI 2013 reported results from pharmacokinetic (PK) evaluations of currently available and recommended antiretroviral options.

Quirine Fillekes and colleagues from the Children with HIV in Africa – Pharmacokinetics and Adherence of Simple ARV Regimens (CHAPAS)-1 trial showed findings from a sub-study to evaluate whether dose escalation of nevirapine (NVP) is appropriate in young children.

Young children metabolise NVP faster than older children or adults, increasing the potential for inadequate NVP plasma levels with dose escalation. This could lead to slow viral load suppression and possible treatment failure.

In this study, 211 HIV positive Zambian children, aged 3 months to 14 years, were randomised to start ART in accordance with WHO 2006 weight-band dosing, using full dose twice-daily NVP, or with two week NVP dose escalation. Children received either a NVP-containing fixed dose combination (FDC) generic tablet immediately or started with the FDC in the morning with a two nucleoside dual combination tablet in the evening, for the dose escalation period.

Samples were obtained 2 weeks after starting NVP, 3-4 hours post morning dose for single sample PK. NVP plasma levels were measured using high-performance liquid chromatography (HPLC), with a lower limit of quantification of <0.05 mg/L. Plasma levels were defined as subtherapeutic at <3.0 mg/L. Viral load was measured, where stored samples were available, at weeks 4 (n=62) and 48 (n=121).

A total of 162 (77%) children had week 2 samples available; 45 and 117 children were aged <2 and >2 years (with similar proportions in each randomisation group). At baseline, the children were a median age, weight and CD4% of 5.2 years (IQR 1.5-8.7) years, 13.0 kg (8.1-19.0) and 13% (8-18) respectively.

In children <2 years old the median NVP levels at week 2 were 5.3 mg/L (IQR 4.2-9.0) for the group receiving full dose vs 4.8 mg/L (IQR 2.9-6.4) for those in the dose escalated group, p <0.41. In children > 2 years, the difference in these levels was more pronounced, respectively 10 mg/L (IQR 7.9-12.2) vs 5.0 mg/L (IQR 3.9-6.6), p=0.001.

The investigators noted that statistical power to detect interactions between the dosing strategy and subtherapeutic concentrations was limited. But results suggested that the younger children in the dose escalated group had the largest proportion with subtherapeutic concentrations, p=0.05 versus older children in the dose escalated group.

There was no difference between week 2 NVP plasma concentrations in those with viral load >250 copies/mL vs <250 copies/mL at either week 4, p = 0.97; or week 48, p = 0.40. At week 4, 43% in the full dose vs 32% in the dose escalated group had viral load <250 copies/mL, p = 0.43; at week 48, 72% versus 75% did so, p=0.84.

All11/162 children with grade 1/2 rash were aged >2 years, p = 0.04, and 10 were in the full dose group, p=0.009. In children >2 years, the median NVP plasma concentration was 15.1 mg/L (10.4-19.6) in those with rash (n=11) vs 6.8 (9.7-4.5) mg/L in those without rash (n=106), p <0.001.

The investigators concluded that although children >2 years should continue to receive an escalated dose of NVP, full dose at ART initiation should be considered for younger children.

In the second study, Jorge Pinto and colleagues from the IMPAACT P1083 group looked at the WHO recommended paediatric weight band dosing schedule of lopinavir/ritonavir (LPV/r). Although WHO weight band dosing is now standard in many resource-limited settings, there are no data describing drug exposure or safety profiles in infants and children dosed in accordance with this guidance.

IMPAACT P1083 is a phase 1/2 trial to evaluate short-term PK, safety, efficacy and tolerability of LPV/r in HIV-positive infants and children weighing >3 to<25 kg. The heat-stable paediatric LPV/r 100/25 mg tablet or the liquid 80/20 mg/mL formulations were used, dosed according to the WHO weight band dosing schedule. LPV/r was given in regimens with two NRTIs as background therapy.

After 4 weeks of receiving LPV/r intensive 12-hour PK samples were collected at 0, 2, 4, 6, 8, and 12 hours post observed dose. LPV/r plasma concentrations were measured by HPLC. The target geometric mean (GM) for LPV AUC0-12 was 80 (range 40-160) mcg.h/mL.

The study plans to enrol 94 subjects to have a target of 85 evaluable infants and children from Brazil, Thailand and USA.

At the time of this interim analysis, 48 subjects, with a median age 4.24 (range 0.4- 12.9) years CD4 percent of approximately 25% and viral load 5.0 log10 copies/mL, had intensive PK results. Thirty subjects received the liquid formulation. The median dose was 316 mg/m2.

The geometric mean of LPV parameters were: AUC 119.8 mcg*hr/mL (range 29.3-261); Cmin 5.5 mcg/mL (range 0.03- 13.83); Cmax 13.42 mcg/mL (range 3.84, 29.17) and CL/F 3.36 L/hr/m2 (range0.14-11.62).

The investigators reported no > grade 3 adverse events considered to be associated with the study drug, but two grade 3 events that were possibly associated. For the 42 children with week 24 results available, the mean change from baseline to week 24 in log10 copies/mL viral load was –2.1 (SD 1.6), and in CD4 percent was 5.3% (SD 6.2).

They concluded that LPV/r, prescribed according to the WHO weight band dosing regimen in children, achieved adequate plasma exposure. Exposure was higher than seen in adults with soft gel capsules but the treatment was well tolerated and the preliminary efficacy data were favourable.

References:

1. Fillekes Q et al. Is nevirapine dose escalation appropriate in young African HIV+ children? 20th CROI, 3-6 March 2013, Atlanta, GA, USA. Poster abstract 975a.
2. Pinto J et al. Pharmacokinetics of lopinavir/ritonavir dosed according to the WHO pediatric weight band dosing guidelines: Interim Results from IMPAACT P1083. 20th CROI, 3-6 March 2013, Atlanta, GA, USA. Poster abstract 976.