Assessment of the Effects of Age and Renal Function on Pharmacokinetics of Bazedoxifene in Postmenopausal Women.

Bazedoxifene (BZA), a chemically distinct selective estrogen receptor modulator, has demonstrated efficacy and long-term safety in phase 3 placebo-controlled studies for prevention and treatment of osteoporosis. Here, we assessed the potential effects of age and renal function on BZA pharmacokinetics in healthy postmenopausal women (aged 55-84 years; CLcr, 32-109 mL/min). This was an open-label, single-dose, parallel, nonrandomized inpatient study conducted in healthy postmenopausal women and postmenopausal women with impaired renal function. Each subject received a single oral dose of BZA in a 20-mg tablet. Twenty-six subjects were enrolled: 8 in each of 3 age groups (55-64 years, 65-74 years, ≥75 years) and 2 (aged 71 and 75 years) with mild renal impairment; all subjects received treatment and completed the study. Age-related changes in pharmacokinetics were apparent. Although the correlation was modest (R2 = 0.28), BZA CL/F decreased steadily with age, such that the oldest group (>75 years) had a mean CL/F 60% less than the youngest group (55-64 years). Over the observed range of CLcr, there was a weak positive correlation (R2 = 0.19) between BZA CL/F and CLcr.

Assessment of Relative Bioavailability of Moroctocog Alfa and Moroctocog Alfa (AF-CC) in Subjects With Severe Hemophilia A.

An open-label, single-dose, randomized, two-period, crossover study comparing the pharmacokinetics of factor VIII activity in plasma (FVIII:C) after administration of an albumin-free presentation of moroctocog alfa (test) and moroctocog alfa manufactured using the previous technique (reference) was conducted in 30 (25 evaluable) male subjects who had severe hemophilia A (FVIII:C < 1 IU/dL). Blood samples were collected for 48 h after administration of each dose. FVIII: C was assayed using a chromogenic substrate assay. The FVIII:C pharmacokinetic parameters were calculated using noncompartmental analysis. The presentations would be bioequivalent if the 90% confidence limits of the ratio of the geometric mean values of AUCinf and recovery fell within the interval of 80-125%. The bioequivalence criteria were met. A total of 10 treatment-related adverse events were observed in a total of nine subjects. All were mild and none was determined to be related to administration of study medication.

Assessment of relative bioavailability of two presentations of moroctocog alfa (AF-CC) in subjects with moderately severe or severe hemophilia A.

UNLABELLED: An open-label, single-dose, randomized, two-period, cross-over study comparing the pharmacokinetics of factor VIII activity in plasma ( FVIII: C) after administration of a new presentation of moroctocog alfa containing 3,000 IU in a dual-chamber syringe and the combined contents of approved 1,000 and 2,000 IU vials was conducted in 16 male subjects who had moderately severe or severe hemophilia A (FVIII:C ≤2 IU/dL). Blood samples were collected for 72 hours after administration of the dose. FVIII: C were assayed using a chromogenic substrate assay in a central laboratory. The FVIII: C pharmacokinetic parameters were calculated using noncompartmental analysis. The dual-chamber syringe would be bioequivalent to the combined contents of the vials if the 90% confidence limits of the ratio of the geometric mean values of AUCinf , and Cmax fell within the interval of 80-125%. The bioequivalence criteria were met. A total of seven treatment related adverse events were observed in a total of five subjects. All were mild and none was determined to be related to administration of study medication.

Use of a clinically derived exposure-response relationship to evaluate potential tigecycline-Enterobacteriaceae susceptibility breakpoints.

Potential tigecycline-Enterobacteriaceae susceptibility breakpoints were evaluated using 2 approaches, which differed in the nature of the probabilities assessed by MIC value. Using a previously derived tigecycline population pharmacokinetic model and Monte Carlo simulation, a probability density function of steady-state area under the concentration-time curve for 24 h (AUC(SS(0-24))) values for 9999 patients was generated. AUC(SS(0-24)) values were divided by clinically relevant fixed MIC values to derive AUC(SS(0-24))/MIC ratios, which were used to calculate the clinical response expectation by MIC value based upon a logistic regression model for efficacy (1st approach). For the 2nd approach, the probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment was calculated as the proportion of patients with AUC(SS(0-24))/MIC ratios greater than the threshold value of 6.96, the PK-PD target associated with optimal clinical response. Probabilities of clinical response and PK-PD target attainment were poorly correlated at MIC values >0.25 mg/L. For instance, the median probability of clinical success was 0.76, whereas the probability of PK-PD target attainment was 0.27 at an MIC value of 1 mg/L, suggesting that the probability of PK-PD target attainment metrics underestimates the clinical performance of tigecycline at higher MIC values.

Evaluation of tigecycline penetration into colon wall tissue and epithelial lining fluid using a population pharmacokinetic model and Monte Carlo simulation.

The objective of these analyses was to assess the penetration of tigecycline into colon wall tissue and epithelial lining fluid (ELF). The analyses included data from subjects without infection (phase 1) and patients with intra-abdominal infections (phase 2/3). Steady-state serum samples were collected from all subjects/patients (n = 577), while colon wall specimens (n = 23) and ELF specimens (n = 30) were obtained from subjects without infection. Tissue and serum data were simultaneously comodeled by using the BigNPAG program, and a four-compartment, open model with zero-order intravenous input and first-order elimination was employed. To examine the full range of tissue penetration and the associated probabilities of occurrence, a 9,999-subject Monte Carlo simulation was performed with two outputs, one for ELF penetration and one for colon wall tissue penetration. Data were well fit using models described above, with all r(2) values above 0.95. For subjects without infection, the median (5th and 95th percentiles) colon wall and ELF penetration ratios were 1.73 (0.160 and 199) and 1.15 (0.561 and 5.23), respectively. Simulation results predict that tissue penetration varies considerably and likely explain unexpected clinical outcomes for those patients infected with strains at margins of the MIC distribution.