f Relebactam (REL [MK-7655]) is a novel class A/C -lactamase inhibitor intended for use with imipenem for the treatment ofGram-negative bacterial infections. REL restores imipenem activity against some resistant strains of Klebsiella and Pseudomonas. In this multicenter, double-blind, controlled trial (NCT01506271), subjects who were >18 years of age with complicated intra-abdominal infection were randomly assigned (1:1:1) to receive 250 mg REL, 125 mg REL, or placebo, each given intravenously (i.v.) with 500 mg imipenem-cilastatin (IMI) every 6 h (q6h) for 4 to 14 days. The primary efficacy endpoint was the proportion of microbiologically evaluable (ME) subjects with a favorable clinical response at discontinuation of i.v. therapy (DCIV). A total of 351 subjects were randomized, 347 (99%) were treated, and 255 (73%) were ME at DCIV (55% male; mean age, 49 years). The most common diagnoses were complicated appendicitis (53%) and complicated cholecystitis (17%). Thirty-six subjects (13%) had imipenem-resistant Gram-negative infections at baseline. Both REL doses plus IMI were generally well tolerated and demonstrated safety profiles similar to that of IMI alone. Clinical response rates at DCIV were similar in subjects who received 250 mg REL plus IMI (96.3%) or 125 mg REL plus IMI (98.8%), and both were noninferior to IMI alone (95.2%; one-sided P < 0.001). The treatment groups were also similar with respect to clinical response at early and late follow-up and microbiological response at all visits. Pharmacokinetic/pharmacodynamic simulations show that imipenem exposure at the proposed dose of 500 mg IMI with 250 mg REL q6h provides coverage of >90% of carbapenem-resistant bacterial strains.
P ediatric drug development is challenging and fairly unique in several aspects. 1 Most of the development programs have just one chance to perform an informative set of trials. After that, industry does not have any financial incentive. Pharmacokinetic (PK) information is useful in (1) selecting dose range for future studies; (2) assessing drug exposure for efficacy and safety purposes, especially by matching exposures to adults, and ultimately (3) supporting dosing approval. Different guidances were published to explain the role of pediatric studies under various conditions and the growth and developmental changes in factors influencing absorption, distribution, metabolism, and elimination of drugs in the pediatric population. 2,3 Even though sample size justification is provided for pediatric efficacy studies, the sample size selection for pediatric PK and safety studies has been vastly different without clear justification. As a consequence, either the pediatric exclusivity determination or the approval decision was affected. Hence, there is a need for a uniform definition of study quality for PK studies.One of the important goals of the pediatric PK study is to ensure the precise estimate of important PK parameters, such as clearance and volume of distribution, to justify the choice of a safe and effective dose from a PK perspective. To achieve this goal, a standard regulatory requirement has been drafted and communicated to the sponsors, where applicable, as follows:The study must be prospectively powered to target a 95% CI [confidence interval] within 60% and 140% of the geometric mean estimates of clearance and volume of distribution for DRUG NAME in each pediatric sub-group with at least 80% power. This report describes methodological details and expectations to fulfill this requirement based on either a noncompartment analysis (NCA) or a population PK (popPK) modeling approach. In the case of NCA analysis, we assume PK parameters have been robustly evaluated with an appropriate blood sampling strategy at the individual patient level. In some cases, the requirement for sample size is primarily driven by safety objectives where a minimum number of participants are required for safety evaluation, and this number may be more than that for PK objectives. Nevertheless, the same language will be communicated to the sponsors even if the planned sample size for safety objectives is more than that for PK objectives. A review of 3 pediatric clinical trials is presented to illustrate the feasibility of complying with the proposed quality standard. Finally, the potential impact of the quality standard on pediatric drug development is discussed. MethodIn this section, detailed steps to achieve the target, 95% CI within 60% and 140% of the geometric
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