Comparison of pharmacokinetics of originator and generic liquid formulations and split tablets in Malawian children
10 February 2006. Related: Conference reports, Paediatric care, ICAAC 45th Washingon 2005.
Polly Clayden, HIV I-Base
Malawian national guidelines include divided Triomune (fixed combination of d4T, 3TC and nevirapine) tablets to treat paediatric HIV. Children are dosed by weight in 1/4 tablet multiples.
Corbett and colleagues from the University of North Carolina presented findings from a 3-way crossover study comparing pharmacokinetics (PK) of d4T, 3TC and nevirapine in HIV positive children In Lilongwe, Malawi. The children received either divided Triomune 40 (GT), generic liquids (GL) or trade liquids (TL).
The children were divided into three groups by weight: Group 1, 8 to <12kg, dose 1/4 tablet BID; Group 2, 18 to <22kg, 1/2 tablet BID; and Group 3, 28 to <32kg, 3/4 tablet BID and had been taking GT for a minimum of three months. Children were then randomised to receive GT, GL or TL and 6 hour PK was performed after 10 days of receiving each formulation.
The study included 18 children (11 female and 7 male) with a median age of 7 years (range: 0.08-13.6 years) and a median weight of 19kg (range: 9-30.5kg). Their median CD4 was 383 cells mm3 (range: 13-1415 cells mm3) and viral load 399 copies/mL (range: 261-2,837,779 copies/mL).
The authors reported the following geometric mean ratios (90% CI) for Cmax and AUC:
| GT/GL | GT/TL | GL/TL | |
| 3TC | 0.86 (0.71,1.05) | 0.79 (0.58,1.08) | 0.91 (0.77,1.10) |
| 0.91 (0.76, 1.09) | 0.84 (0.65, 1.08) | 0.92 (0.79, 1.08) | |
| d4T | 0.86 (0.61, 1.21) | 0.86 (0.57,1.30) | 1.00 (0.66,1,53) |
| 1.05 (0.80,1.39) | 0.94 (0.66,1.35) | 0.90 (0.68,1.17) | |
| NVP | 1.02 (0.87,1.20) | 1.04 (0.87,1.24) | 1.02 (0.83,1.25) |
| 1.02 (0.87, 1.19) | 1.06 (0.91,1.23) | 1.04 90.87,1.23) |
The authors found that in all dosing groups NVP met the definition for bioequivalence (BEQ) but neither 3TC nor d4T met the definition despite statistically significant differences. They also noted that T-max was delayed for 3TC and d4T compared to both liquid formulations.
Additionally there was clinical difference in 3TC and d4T exposures in children in Group 1 receiving the GT compared to both liquids. In the other two groups, although not BEQ, they reported less clinical difference.
They noted that compared to historical US PK data 3TC and d4T TL concentrations were lower and NVP concentrations higher in Malawian children vs north American children.
They concluded that based on PK, liquid formulations are better for smaller children, but for larger children quartered multiples of fixed dose combinations are a reasonable option.
Reference:
Corbett A, Hosseinipour M, Nyirenda J et al. Pharmacokinetics between trade and generic liquid and split tablet formulations of lamivudine, stavudine and nevirapine in HIV infected Malawian children. 45th ICAAC, Washington, 2005. Abstract H-1905