Antiretrovirals that are safe, effective, and less expensive are critical to the treatment of HIV in resource-poor countries such as Malawi where >12% of the population is infected, ~140,000 are receiving ARVs and the annual GNP is $190USD [3
]. Of those infected, approximately 10% are children <15 years old [18
]. Ten percent of infected children are taking antiretroviral therapy; however, this constitutes only one-half of the children in need of treatment, who mostly rely on the government for their care. [17
]. The Malawi Ministry of Health guidelines, which was developed in 2003, provided for the use of quartered multiples of generic fixed dose combinations for children, and provided children with access to these medications. Although splitting unscored fixed dose combination tablets is not an optimal method of drug delivery, the guidelines for dosing Malawian children were thoughtfully developed based on the availability of resources. This study provides PK data to support this practice for some, but not all, children.
One study examining split dose GPO-VIR S30 (fixed dose combination of stavudine 30mg, lamivudine 150mg, and nevirapine 200mg) in Thai children found only one of 34 children to have suboptimal nevirapine concentrations, with 12 of 13 children using this as their first line ARV regimen having undetectable viral loads [19
]. However, previous pharmacokinetic evaluations by Ellis, et al in African children using split tablets of Triomune have demonstrated that some do not achieve adequate NVP concentrations [7
]. Direct comparison of these studies cannot be performed, as two ethnically different populations were given two different generic fixed dose formulations. The low nevirapine exposures in the Ellis study do, however, further support the suboptimal nevirapine exposures seen in 50% of our subjects. Additionally, in both investigations in African children, the majority of patients with low nevirapine exposures were younger children. No studies to date have performed intra-patient comparisons for Triomune quartered tablets, individual generic and individual trade liquid products. Therefore, this study aimed to evaluate the pharmacokinetics of 3TC, d4T, and NVP in HIV-infected children receiving quartered multiples of Triomune 40™ as compared to the equivalent doses of the generic liquid formulations and the NIH recommended dose for children (at the time the study was conducted) using the FDA-approved trade products. Since little is known about the population differences in drug disposition, the latter comparison allowed us to evaluate exposures of drug from trade product in the Malawian population to Western cohorts.
The current investigation demonstrated that, for most children, the use of a split generic fixed dose combination provided similar exposures to both generic and trade liquids. This occurred despite the visible differences in size of each quarter tablet split with a commercial tablet splitter. Unpublished data from our lab determined that although Triomune 40™ had similar nevirapine content to Viramune tablets, it took longer to dissolve in an aqueous solution (25% less drug available at 6 hours).
Generally, 3TC exposures were lower for generic products as compared to trade formulations. This difference was driven by the consistently lower concentrations of 3TC in Group 1 subjects (8-<12kg). Due to trade liquid dosing being 11% higher than the generic dosing, this suggests underdosing of this group for 3TC. Stavudine results were highly variable, with subjects in Group 3 (28-<32kg) having the lowest concentrations when given the generic tablet formulation. Due to the median mg/kg dosing for all groups being similar (1.9, 2.1, and 2.1mg/kg for Groups 1, 2, and 3, respectively), this does not appear to be a phenomenon of underdosing.
Perhaps most concerning are the NVP data, where 10 of the 13 episodes of subtherapeutic NVP concentrations (<3000ng/mL) occurred in Group 1. This difference is likely due to a suboptimal mg/kg dosing strategy . Group 1 subjects were given lower doses compared to Groups 2 and 3. Comparing current mg/m2 dosing guidelines, children in group 1 were given a median (range) dose of 217 (177,312) mg/m2 compared to children in groups 2 and 3 who were given nevirapine at 271 (204,356) mg/m2 and 286 (226,304) mg/m2, respectively.
Overall, product source also appeared to affect drug exposure. Although the GL dosing strategy was 13% lower than the TL dosing strategy, exposures with this generic formulation were approximately 30% lower than with the trade formulation. We did not perform any testing on these formulations to determine whether differences in drug content could explain this finding.
This investigation also found some differences in the trade liquid formulation exposures in Malawian children as compared to Western cohorts [20
]. Lamivudine and stavudine Cmax
exposures with trade liquid were both 39% lower in Malawians, while nevirapine exposures were 100% higher than that reported in Western cohorts [20
]. Although this comparison was not an objective in this investigation, it does warrant discussion of the potential pharmacokinetic differences in these populations with consideration for safety and efficacy.
Since 3TC and d4T are readily absorbed, eliminated renally and have no liver metabolism, the reason for these differences in exposure is unclear. This may be due to differences in age, weight, nutritional status, or maturation of the gastrointestinal tract and/or renal system between the populations. The differences in NVP have been seen previously in an adult population, and may be due to drug metabolism enzyme or transporter differences [6
]. Studies are currently underway to assess what contribution P-glycoprotein and CYP450 polymorphisms may have on differences in NVP exposure in the Malawian population.
These data provide some support for the use of Triomune 40™ using these doses for children in Groups 2 and 3 [18-<22kg and 28-<32kg]. Based on the low concentrations of 3TC and NVP in children in Group 1 [8-<12kg], the investigators do not feel that dosing Triomune 40™ ¼ tablet twice daily will provide adequate concentrations. Based on these data and other investigations, the Malawi Ministry of Health changed the guidelines for treating HIV-infected children in 2006. Currently, it is recommended to use Triomune 30™ (30mgd4T/150mg3TC/200mgNVP) in lieu of the Triomune 40™ formulation [23
]. Overall these new guidelines provide higher daily doses of each antiretroviral in children 8->12kg and avoid the underdosing that was found in this PK analysis. Additional generic pediatric formulations, such as Triomune Baby (6mg d4T/30mg 3TC/50mg NVP) and Triomune Junior (12mg d4T/60mg 3TC/100mg NVP), allow whole tablets to be administered to children [24
]. The 3rd
Edition of these guidelines, currently under evaluation in Malawi, may recommend use of these newer products and be the best alternative to liquid formulations. However, in children 18-<22 and 28-<32kg, split dose Triomune is an appropriate alternative.