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Antiretrovirals, Doses and Formulations for Children

July/August 2013

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Maraviroc

Maraviroc (MVC) is a CCR5 antagonist, approved to treat adults and adolescents aged 16 years or more with CCR5-tropic HIV but not yet approved for paediatric use.

Data were presented from 94 participants in the ongoing A4001031 study in treatment-experienced children and adolescents aged 2 to <18 years.6

This is an open-label, two-stage (stage 1: dose-finding; stage 2: safety/efficacy), age-stratified, non-comparative, multicentre study to evaluate the safety, tolerability, and PK of MVC plus optimised background therapy.

Participants are enrolled into one of four cohorts by age and formulation: cohort 1, >2 to <6 years/liquid (n=13); cohort 2, >6 to <12 years/tablet (n=27); cohort 3, > 6 to 12 years/liquid (n=12), and cohort 4, > 12/tablet (n=42).

Those eligible have viral load >1000 copies/mL, on stable or no therapy and have experienced >6 months in at least two ARV classes.

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Dosing is complex and determined by body-surface area (BSA) and concomitant medications. Dose adjustment occurred if average concentrations were <100 ng/mL at Week 2. Doses ranged from 50-450 mg twice daily.

A total of 75/94 participants were followed for 48 weeks. At the time of analysis 49 were still on treatment and 26 discontinued MVC, 14 with virological failure and evidence of non-adherence -- which was more frequent in adolescents -- and 3 participants with virological failure had tropism shift. Of those remaining on treatment, 52% and 40% had viral load <400 and 50 copies/mL respectively.

AEs occurred in 60 (63%) participants and 10 (10.6%) were grade 3 or 4. There were no deaths and 3 discontinuations due to AEs. Most common (>10%) AEs were: infection and infestations (49%), gastrointestinal disorders (36%), nervous system disorders (14%), reproductive system and breast disorders (13%), and skin and subcutaneous tissue disorders (12%).

MVC PK from this study was presented separately.7 This sub study using PK profiles from 51 participants found BSA-based dosing with CYP3A4 inhibitors scaled from the 300 mg adult dose provides MVC exposures achieving the target Cavg >100 ng/mL in all cohorts.

Non-inhibitor ART regimens are still under evaluation and PK data suggests that doses are likely to be higher than the initial adult BSA scaled dose.

Enrollment in A4001031 will continue out to five years.


Efavirenz

Efavirenz (EFV) plus NRTI backbone combination is the preferred WHO first line antiretroviral therapy for HIV-positive children more than 3 years and weighing above 10 kg.

WHO weight band dosing reduces the proportion of children with EFV concentrations below target compared to FDA, but this is achieved with a higher proportion having concentrations above target and in turn a higher risk of toxicity, according to a study comparing the two dosing guidelines using a population PK approach.8 See Table 2.


Table 2: Efavirenz Dosing Guidelines
Dose Body weight
FDA WHO (2010/2013)*
200 mg 10 to <15 kg 10 to <14kg
250 mg 15 to <20 kg 14 to <25
300 mg 20 to <25 kg
350 mg 25 to <30 kg 25 to <35
400 mg 30 to 40 kg
600 mg > 40 kg > 35 kg

* The study used 2010 dosing guidance -- this is unchanged in the 2013 revision.


This analysis included EFV plasma concentration data from 190 children (623 plasma samples); 40 had 24-hour PK sampling data available. EFV was given according to FDA weight band recommendations. Population PK was estimated using nonlinear mixed effects modelling.

Median age was 7.2 years (0.1* to 12.2), bodyweight 16 kg (5 to 42), and efavirenz dose 300 mg (200-600). *The investigators noted that this child at the lowest end of the range first received dual NRTI before starting EFV at 5.4 years.

A one-compartment PK model was used with delay absorption. Weight influenced EFV apparent oral clearance and volume of distribution and allometric scaling significantly reduced the interindividual variability.

The estimated median AUC0-24 was 49 mg/L.hr (8 to 296). A predicted EFV C12 was 2.3 mg/L (0.07 to 11.9). Of 190 children, 16 (8%) had predicted EFV C12 below 1 mg/L (subtherapeutic range) and 12 (6%) above 4 mg/L (toxic range) with FDA dosing. No serious adverse events were reported.

Simulations predicted similar proportions of children with C12 between 1 mg/L and 4 mg/L with both dosing guidelines. Proportions of children with C12 in the subtherapeutic range were reduced across all weight bands with WHO compared to FDA dosing, respectively: 8 vs 16%, 11 vs 14%, 12 vs 16% and 8 vs 15% in the 14 to <15 kg, 15 to <20 kg, 25 to 32.5 kg and 35 to 40 kg groups; but proportions in the toxic range increased, respectively: 39 vs 25%, 33 vs 24%, 28 vs 21% 42 vs 21%.

A previous study of Thai children an 11% frequency of CYP2B6 TT genotype (EFV concentration >6 mg/L), genotypes were not determined in this one but several children had EFV concentrations >6 mg/mL which could be explained by this phenomenon.

Safety data on EFV in children dosed according to the WHO weight bands are needed.


Lopinavir/Ritonavir

Using 70% of lopinavir/ritonavir (LPV/r) standard dose in heat stable tablet formulation for maintenance therapy was non-inferior to standard dose in a Thai study.9

This was a multicentre, randomised, open-label trial conducted at 11 sites in Thailand. Children and adolescents aged < 18 years weighing 25-50 kg with viral load <50 copies/mL were randomly assigned to FDA -recommended standard dose or low dose of LPV/r.

LPV/r doses for children 25 to 35 kg were 300/75 mg or 200/50 mg, and >35 to 50 kg were 400/100 mg or 300/75 mg twice daily. The primary endpoint was the proportion of children with viral load <50 copies/mL at 48 weeks. Secondary endpoints were LPV Ctrough and the proportion of children with dyslipidemia.

The study enrolled 199 children, with mean age of 13.4 years (SD 2.2) years, and CD4 of 787 (319) cells/mm3; 98 were randomised to standard and 101 to the low dose arm. The NRTI backbones were AZT/3TC (47%), AZT/ddI (18%), TDF/3TC (16%) and others (20%).

Loss to follow up was 7 (3.5%) participants -- 3 in the standard and 4 in the low dose arms.

At 48 weeks, by intention to treat analysis, the proportions of participants with viral load <50 copies/mL were 91.8% in the standard and 88.1% in the low dose arms, difference -3.7% (95% CI -12.0 to 4.6%), p=0.38. Eight participants had viral load >400 copies and factors associated with this were poor adherence (aOR 3.3) and weight 35 to 50kg (aOR 3.6).

Median LPV Ctrough at week 48 were 6.9 (range 0.3. to 20.4) and 5.2 (0.2 to 11.8) mg/dL, standard and low dose respectively. Fourteen (7.3%) had Ctrough < 1 mg/dL (4 in standard and 10 in low dose arms, p = 0.1).

More children in the standard arm had cholesterol > 200 mg/dL (34.4 vs 20.6%, p=0.03) and triglyceride > 150 mg/dL (60.4 vs 44.3%, p =0.03) than those in the low dose arm.

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This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
 

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