TAG 2010 Pipeline Report
Protease inhibitors, however, have poor bioequivalence with crushed tablets. In a recent study, investigators observed significantly lower exposure with crushed lopinavir/ ritonavir compared to the reference product.27 For young nevirapine-exposed children, lopinavir/ritonavir “sprinkles” are currently being studied in the Children with HIV in Africa—Pharmacokinetics and Acceptability of Simple Antiretroviral Regimens trials.28 These trials have looked at or are looking at simplifying antiretroviral regimens—for example, toxicity and adherence/acceptability profiles of new pediatric FDCs that contain abacavir or zidovudine rather than stavudine, and simplification strategies such as once-daily regimens and whether it is necessary to dose-escalate nevirapine. The trials use WHO weight-band tables. Approval of Pediatric Formulations There are now considerable incentives and/or penalties from regulatory agencies to ensure that any new drug that may be of benefit to children must be studied in children. This is mandatory on the part of both the FDA, which also extends six-month patent protection to companies that perform requested pediatric studies (voluntary), and the European Medicines Agency (EMA), which enforces penalties for companies that do not provide a pediatric investigational plan as part of their application (or request a waiver). 29 Companies must include PK data for all age groups of children, efficacy, tolerability, and differences in side effects. They must have stability and palatability data for formulations and demonstrate that they are able to achieve PK targets associated with efficacy in adults. Most pediatric development programs take a staggered approach, starting with the older cohorts of children and working down in age. The studies are conducted in children as soon as there are sufficient data from studies in adults. Applications for generic formulations must demonstrate bioequivalence. A single product needs to be compared to the reference product (innovator). Generic FDCs need to be compared to the individual reference drugs taken together. Preferred bioequivalence studies are randomized, single-dose, two-way crossover studies. Bioequivalence studies need not be done in children. Dissolution testing is required when evaluating solid or suspension formulations to assure reproducible drug release. 38