Animal-to-Human Dose Translation of Obiltoxaximab for Treatment of Inhalational Anthrax Under the US FDA Animal Rule.

Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax under the US Food and Drug Administration's (FDA) Animal Rule. The human dose was selected and justified by comparing observed obiltoxaximab exposures in healthy and infected New Zealand White rabbits and cynomolgus macaques to observed exposures in healthy humans, to simulated exposures in healthy and infected humans, and to serum PA levels in infected animals. In humans, at 16 mg/kg intravenous, obiltoxaximab AUC was >2 times that in animals, while maximum serum concentrations were comparable to those in animals and were maintained in excess of the concentration required for PA neutralization in infected animals for 2-3 weeks. Obiltoxaximab 16 mg/kg in humans provided exposure beyond that of 16 mg/kg in animals, ensuring a sufficient duration of PA neutralization to allow for adaptive immunity development. Our approach to dose translation may be applicable to other agents being developed under the Animal Rule.

Mixed-effects modelling to quantify the effect of empagliflozin on renal glucose reabsorption in patients with type 2 diabetes.

AIMS: To quantify the effect of the sodium-glucose co-transporter 2 inhibitor, empagliflozin, on renal glucose reabsorption in patients with type 2 diabetes, and to evaluate covariate effects, using a mechanistic population pharmacokinetic-pharmacodynamic (PK-PD) model. METHODS: Four phase I/II trials were used for model development. Empagliflozin's PK characteristics were characterized by a two-compartmental model with sequential zero- and first-order absorption. Urinary glucose excretion (UGE) was described as dependent on renal glucose filtration and reabsorption; splay of the glucose reabsorption/excretion curves was considered. The modelling assumed that empagliflozin lowers the maximum renal glucose reabsorption capacity and, thereby, the renal threshold for glucose (RTg). Covariate effects were investigated using a full covariate modelling approach, emphasizing parameter estimation. RESULTS: The PK-PD model provided a reasonable description of the PK characteristics of empagliflozin and its effects on UGE across a range of renal function levels. Its parameters are consistent with reported values for renal physiology. Using this model, the effect of empagliflozin on renal glucose reabsorption was quantified. Steady-state empagliflozin doses (1, 5, 10 and 25 mg) reduced RTg from 12.5 mmol/L [95% confidence interval (CI) 12.0, 13.1] to 5.66 (95% CI 4.62, 6.72), 3.01 (95% CI 2.33, 3.69), 2.53 (95% CI 1.83, 3.14) and 2.21 (95% CI 1.47, 2.84) mg/dl, respectively. Covariate analysis showed the effect of empagliflozin on UGE was not influenced, to a clinically relevant extent, by sex, age or race. CONCLUSIONS: A method for characterizing renal glucose reabsorption was developed that does not require complex glucose clamp experiments. These analyses indicate that empagliflozin provided concentration-dependent RTg reductions, with 10 and 25 mg providing near-maximum RTg-lowering.

Plasma pharmacokinetics and tissue distribution of the breast cancer resistance protein (BCRP/ABCG2) inhibitor fumitremorgin C in SCID mice bearing T8 tumors.

Multidrug resistance (MDR) remains a major obstacle in the treatment of human cancers. The recently discovered breast cancer resistance protein (BCRP/ABCG2) has been found to be an important mediator of chemotherapeutic MDR. Fumitremorgin C (FTC) is a selective and potent inhibitor of BCRP that completely inhibits and reverses BCRP-mediated resistance at micromolar concentrations. We report a study of the pharmacokinetics and tissue distribution of FTC when administered intravenously (IV) at a dose of 25 mg/kg to female SCID mice bearing the BCRP-overexpressing human ovarian xenograft Igrov1/T8 tumors. Plasma pharmacokinetics and tissue distribution of FTC in various organs and tissues were studied. In addition, the effect of FTC administration on the expression of BCRP in T8 tumors was also assessed by RT-PCR. Administration of a single FTC IV dose did not appear to cause any major toxicities. The resulting pharmacokinetic data were fit to a two-compartment model using NONMEM and the FTC clearance was determined to be 0.55 ml/min (25.0 ml/min/kg) with a 56% inter-animal variability. Area under the plasma concentration time curve was determined by Bailer's method and was calculated to be 1128+/-111 microg min/ml. FTC was widely distributed in all tissues assayed with highest concentrations found in lungs, liver and kidney in decreasing order, respectively. FTC did not appear to have any effect on the expression of BCRP in T8 tumors. Less than 2% of the administered dose was recovered in the urine and feces after 24 h, suggesting hepatic metabolism as a primary mechanism of elimination. The current study can be used as a basis for future animal or in vivo studies with FTC designed to further understand the impact of BCRP on drug resistance.