Effect of Body Weight and Age on the Pharmacokinetics of Dihydroartemisinin: Food and Drug Administration Basis for Dose Determination of Artesunate for Injection in Pediatric Patients With Severe Malaria.

For treatment of severe malaria, the World Health Organization recommends 3 mg/kg intravenous artesunate in pediatric patients weighing less than 20 kg. Here we describe the Food and Drug Administration's rationale for selecting 2.4 mg/kg in pediatric patients weighing less than 20 kg based on literature review and independent analyses.

"Development of Fixed Dose Combination Products" Workshop Report: Considerations of Gastrointestinal Physiology and Overall Development Strategy.

The gastrointestinal (GI) tract is one of the most popular and used routes of drug product administration due to the convenience for better patient compliance and reduced costs to the patient compared to other routes. However, its complex nature poses a great challenge for formulation scientists when developing more complex dosage forms such as those combining two or more drugs. Fixed dose combination (FDC) products are two or more single active ingredients combined in a single dosage form. This formulation strategy represents a novel formulation which is as safe and effective compared to every mono-product separately. A complex drug product, to be dosed through a complex route, requires judicious considerations for formulation development. Additionally, it represents a challenge from a regulatory perspective at the time of demonstrating bioequivalence (BE) for generic versions of such drug products. This report gives the reader a summary of a 2-day short course that took place on the third and fourth of November at the Annual Association of Pharmaceutical Scientists (AAPS) meeting in 2018 at Washington, D.C. This manuscript will offer a comprehensive view of the most influential aspects of the GI physiology on the absorption of drugs and current techniques to help understand the fate of orally ingested drug products in the complex environment represented by the GI tract. Through case studies on FDC product development and regulatory issues, this manuscript will provide a great opportunity for readers to explore avenues for successfully developing FDC products and their generic versions.

Impact of the US FDA "Biopharmaceutics Classification System" (BCS) Guidance on Global Drug Development.

The FDA guidance on application of the biopharmaceutics classification system (BCS) for waiver of in vivo bioequivalence (BE) studies was issued in August 2000. Since then, this guidance has created worldwide interest among biopharmaceutical scientists in regulatory agencies, academia, and industry toward its implementation and further expansion. This article describes how the review implementation of this guidance was undertaken at the FDA and results of these efforts over last dozen years or so across the new, and the generic, drug domains are provided. Results show that greater than 160 applications were approved, or tentatively approved, based on the BCS approach across multiple therapeutic areas; an additional significant finding was that at least 50% of these approvals were in the central nervous system (CNS) area. These findings indicate a robust utilization of the BCS approach toward reducing unnecessary in vivo BE studies and speeding up availability of high quality pharmaceutical products. The article concludes with a look at the adoption of this framework by regulatory and health policy organizations across the globe, and FDA's current thinking on areas of improvement of this guidance.

Exposure Matching for Extrapolation of Efficacy in Pediatric Drug Development.

During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the US Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure-matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the 2 patient populations. The main measures were the pediatric PK studies' trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean Cmax and AUC ratios (pediatric/adult) of 0.63 to 4.19 and 0.36 to 3.60, respectively. Seven of the 86 trials (8.1%) had a predefined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti-infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials.

Local delivery of vancomycin for the prophylaxis of prosthetic device-related infections.

PURPOSE: To evaluate the in vivo efficacy and pharmacokinetics of vancomycin delivered from glycerylmonostearate (GMS) implants in a prosthetic-device based biofilm infection model. METHODS: A biofilm infection model was developed in male Sprague-Dawley rats by implanting a vascular graft on the dorsal side of each rat and infecting it with 1.5 x 10(8) cfu/ml Staphylococcus epidermidis. The rats were divided into 3 groups of 6 rats each: 1) the control group that received no antibiotics, 2) the IM group that received multiple IM injections of vancomycin at a dose of 25 mg/kg every 6 h for a total of 12 doses, and 3) the implant group that received GMS implants designed to deliver vancomycin at a total dose of 300 mg/kg for a period of 4 days. The pharmacokinetics of vancomycin was determined from IM and implant groups by analyzing for vancomycin in blood using HPLC. In vivo efficacy was studied by evaluation of the wound site and the prosthetic device upon excision, for evidence of infection in the form of purulent discharge at the wound site and yellowish discoloration of the prosthetic device and inflammation as sign of biofilm formation. Microbiological evaluation on the wound site and the prosthetic device was performed by culturing the swabs at the wound site and the prosthetic device in sterile tryptic soy broth for 36-48 h at 37 degrees C. RESULTS: Vancomycin was successfully delivered in a sustained manner for 100 h from GMS implants and the resulting plasma profile showed that the concentrations, after an initial burst, plateaued at about of 4.77 +/- 1.43 mug/ml with less fluctuations than the IM group in which the plasma concentrations fluctuated between 2.73 +/- 0.94 mug/ml and 19.26 +/- 3.67 mug/ml. Upon excision of the wound site, all the animals in the control group developed infection in the form of purulent discharge and yellowish discoloration of the prosthetic device. However, none of the rats in the implant group showed evidence of infection clearly demonstrating the efficacy of the local delivery system in preventing infection. Systemically delivered vancomycin by IM injections failed to prevent infection in four out of six rats. Microbiological evaluation of the wound site and prosthetic device resulted in isolation of biofilm-producing organisms such as Staphylococcus epidermidis, Enterococcus faecalis, and Staphylococcus aureus. These organisms were isolated in greater number of animals in the control group compared to the IM and implant groups. CONCLUSIONS: The GMS implants as a delivery system for vancomycin were successful in preventing infection in all the animals compared to the IM and control groups demonstrating the efficacy of a local delivery system in a prosthetic device related biofilm infection model.