Pharmacokinetics for generic fixed dose combinations for children are comparable to the branded products

Cipla Pharmaceuticals in India have developed two generic fixed dose combinations (FDC) for children, Pedimune Baby (d4T 6mg; 3TC 30mg; nevirapine 50mg) and Pedimune Junior (d4T 12mg; 3TC 60mg; nevirapine 100mg).

A poster from Raffaella Lhomme and co-workers from the Radboud University Medical Centre, Nijmegen, The Netherlands, reported findings from a pilot study to determine the pharmacokinetic (PK) profile of d4T, 3TC and nevirapine in Pedimune and compare this with the individual branded products.

This was a phase I, comparative, open-label, three-period, single-dose study designed, not as a formal bioequivalence study, but to exclude large differences in bioavailability. Cipla is currently conducting a formal bioequivalence study.

Six HIV-negative adult males were randomised to one of the following regimen sequences: ABC; ACB; BCA; BAC; CAB; CBA. (A = reference, B = Pedimune Baby, C = Pedimune Junior) Single doses of medication (200mg of nevirapine), were administered in three cycles of four weeks each.

An 8-hour PK curve was recorded on day 1 of every cycle post dose. Additionally, blood was sampled on days 2, 3, 4, 8 and 15. Drug levels were measured by validated high performance liquid chromatography.

The authors found that in Pedimune Baby, geometric mean ratios of log-transformed parameters (GMR; % B/A) of the Cmax were 114 (90% CI: 94-138), 112 (90% CI:100-126) and 84 (90% CI: 64-110). GMR of the AUC were 121 (90% CI:106-138), 113 (90% CI: 105-122) and 95 (90% CI:84-107), for d4T, 3TC and nevirapine, respectively.

In Pedimune Junior, GMR (% C/A) of Cmax were 91 (90% CI:67-124), 91 (90% CI: 70-118) and 98 (90% CI:86-111).GMR of AUC (90% CI) were103 (90% CI: 96-109), 99 (90% CI: 91-108) and 91 (90% CI: 73-115), for d4T, 3TC and nevirapine, respectively. GMR were within 80 to 125%.

In this PK study the authors found the profile of d4T, 3TC and nevirapine in Pedimune Baby and Junior to be comparable to the individual branded products. They wrote; Based on the results of this pilot study, it is acceptable to start testing the pharmacokinetics and dosing requirements of Pedimune Baby and Junior in HIV-infected children even though the formal bioequivalence study by Cipla Pharmaceuticals has not yet been completed.

Comment

Obviously, these FDCs are a very welcome development as current practice yields suboptimal levels of nevirapine in a substantial number of children, particularly the very young (see the following two studies).

A small number of children are currently being treated with Pedimune within the CHAPAS 1 phase 1/2 trial in Zambia (sponsored by the MRC in London). This study will include evaluation of PK of nevirapine, d4T and 3TC in two daily paediatric doses of Pedimune in African children with and without malnutrition and in different age groups. It will also look at possible PK interactions between nevirapine and concomitant medications such as rifampicin and fluconazole.

Children on this trial will be randomised to start with Pedimune full dose vs a dose escalation schedule. So far, approximately 25 children have been enrolled (target 200) and early data will be presented at Toronto.

Lhomme R, Dijkema T, Warris A et al. Pharmacokinetics of two generic fixed dose combinations for HIV-infected children (Pedimune Baby & Pedimune Junior) are comparable to the branded products. 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abstract 23..