Relationship Between Plasma Concentrations and Clinical Effects of Cariprazine in Patients With Schizophrenia or Bipolar Mania.

Population pharmacokinetic/pharmacodynamic modeling (via NONMEM) was used to describe longitudinal exposure-response relationships for total cariprazine (sum of cariprazine and its major active metabolites) in 2,558 patients with schizophrenia or bipolar mania. Drug exposure metrics were explored for potential relationships with efficacy and safety end points. Total cariprazine exposures were significantly related to reductions in Positive and Negative Syndrome Scale (PANSS) or Young Mania Rating Scale (YMRS) total scores in schizophrenia or bipolar mania, respectively, via a maximum effect (Emax )-type relationship. Typical steady-state plasma concentrations after 3 and 4.5 mg/day were associated with 50% of maximum typical reductions in PANSS and YMRS total scores, respectively. Time-weighted cariprazine exposures had significant relationships with the probability of common adverse events (AEs). Dose increase was associated with increased efficacy but was also associated with an increase in AEs. Results of these pharmacokinetic/pharmacodynamic analyses support that the recommended dose range (1.5-6 mg/day for schizophrenia and 3-6 mg/day for bipolar mania) provides an appropriate benefit-risk balance between cariprazine efficacy and safety.

Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections.

Ceftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum ß-lactamase inhibitor tazobactam, is approved for treating complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-tazobactam plasma pharmacokinetic data from a recently completed phase 1 trial in pediatric patients (birth to <18 years old) with proven/suspected Gram-negative bacterial infections, along with pharmacokinetic data from 12 adult studies, were integrated into a population pharmacokinetic (popPK) analysis. Two-compartment linear models with first-order elimination described the concentration-time profiles of ceftolozane and tazobactam in pediatric patients well. Renal function and body weight were identified to be significant predictors of ceftolozane-tazobactam pharmacokinetics. Renal function, as measured by the estimated glomerular filtration rate (eGFR), significantly affected the clearance of both ceftolozane and tazobactam. Body weight significantly affected clearance and the distribution volume, also of both ceftolozane and tazobactam. Patients with infections had a 32.3% lower tazobactam clearance than healthy volunteers. Using the final popPK models, simulations of various dosing regimens were conducted to assess each regimen's plasma exposure and the probability of pharmacokinetic/pharmacodynamic target attainment. Based on these simulations, the following doses are recommended for further clinical evaluation in phase 2 pediatric trials for cUTI and cIAI (in patients with an eGFR of ≥50 ml/min/1.73 m2 only): for children ≥12 years old, 1.5 g ceftolozane-tazobactam (1 g ceftolozane with 0.5 g tazobactam), and for neonates/very young infants, infants, and children <12 years old, 20/10 mg/kg of body weight ceftolozane-tazobactam, both via a 1-h intravenous infusion every 8 h.

Population Pharmacokinetic Modeling of Armodafinil and Its Major Metabolites.

Population pharmacokinetic models for armodafinil and its major metabolites, R-modafinil acid and modafinil sulfone, were developed, and selected covariates were investigated. Data from 583 healthy subjects and patients with bipolar I disorder in 11 phase 1-3 studies (8027 concentrations) of armodafinil, given as single or multiple once-daily doses (50- to 400-mg tablet or capsule), were pooled. A previously developed 1-compartment model with first-order absorption without covariate effects was initially applied to pooled phase 1 and 2 data. After covariate analysis, the phase 3 data were pooled with the phase 1 and 2 data set and the model was refined again using a second backward elimination step. Population modeling was performed with NONMEM version 7 with the first-order conditional estimation method. Estimated armodafinil apparent oral clearance (CL/F), volume of distribution (Vc/F), and absorption t½ were 2.01 L/h, 45 L, and 0.226 hours, respectively. Armodafinil CL/F and Vc/F increased with weight; predicted steady-state area under the curve was 16.4% higher and 29.1% lower in a patient weighing 50 or 150 kg, respectively, relative to a 70-kg patient. Female participants had 10.2% lower armodafinil Vc/F compared with male participants. Age, race (white vs nonwhite), health status (healthy vs bipolar I disorder), liver function, and renal function were not statistically significant predictors of armodafinil pharmacokinetics. CL/F and Vc/F for R-modafinil acid and modafinil sulfone were 16.7 L/h and 8.95 L and 6.82 L/h and 12.4 L, respectively. Weight did not affect exposure of either metabolite. These population pharmacokinetic models were from the largest population of adults reported to date and provide a robust characterization of the pharmacokinetics of armodafinil, R-modafinil acid, and modafinil sulfone in adults.

Nonparametric confidence intervals for Tmax in sequence-stratified crossover studies.

Tmax is the time associated with the maximum serum or plasma drug concentration achieved following a dose. While Tmax is continuous in theory, it is usually discrete in practice because it is equated to a nominal sampling time in the noncompartmental pharmacokinetics approach. For a 2-treatment crossover design, a Hodges-Lehmann method exists for a confidence interval on treatment differences. For appropriately designed crossover studies with more than two treatments, a new median-scaling method is proposed to obtain estimates and confidence intervals for treatment effects. A simulation study was done comparing this new method with two previously described rank-based nonparametric methods, a stratified ranks method and a signed ranks method due to Ohrvik. The Normal theory, a nonparametric confidence interval approach without adjustment for periods, and a nonparametric bootstrap method were also compared. Results show that less dense sampling and period effects cause increases in confidence interval length. The Normal theory method can be liberal (i.e. less than nominal coverage) if there is a true treatment effect. The nonparametric methods tend to be conservative with regard to coverage probability and among them the median-scaling method is least conservative and has shortest confidence intervals. The stratified ranks method was the most conservative and had very long confidence intervals. The bootstrap method was generally less conservative than the median-scaling method, but it tended to have longer confidence intervals. Overall, the median-scaling method had the best combination of coverage and confidence interval length. All methods performed adequately with respect to bias.

Lack of pharmacokinetic and pharmacodynamic interactions between a smoking cessation therapy, varenicline, and warfarin: an in vivo and in vitro study.

This study investigated the effect of varenicline on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in 24 adult smokers and compared these findings with data generated using human in vitro systems. Subjects were randomized to receive varenicline 1 mg twice a day or placebo for 13 days and then switched to the alternative treatment after a 1-week washout period. A single dose of warfarin 25 mg was given on day 8 of each treatment period, and serial blood samples were collected over 144 hours postdose. Pharmacokinetic parameters for both (R)- and (S)-warfarin and international normalized ratio (INR) values were determined. Varenicline was assessed as an inhibitor and inducer of human cytochrome P450 activities using liver microsomes and hepatocytes, respectively. Consistent with the in vitro data, no alteration in human pharmacokinetics of warfarin enantiomers was observed with varenicline treatment. The 90% confidence intervals for the ratios of area under the concentration-time curve from zero hours to infinity and peak plasma concentrations were completely contained within 80% to 125%. Warfarin pharmacodynamic parameters, maximum INR, and the area under the prothrombin (INR)-time curve, were also unaffected by steady-state varenicline. Concomitant administration of varenicline and warfarin was well tolerated. Consequently, warfarin can be safely administered with varenicline without the need for dose adjustment.

Comparison of models for average bioequivalence in replicated crossover designs.

Average bioequivalence (ABE) has been the regulatory standard for bioequivalence (BE) since the 1990s. BE studies are commonly two-period crossovers, but may also use replicated designs. The replicated crossover will provide greater power for the ABE assessment. FDA has recommended that ABE analysis of replicated crossovers use a model which includes terms for separate within- and between-subject components for each formulation and which allows for a subject x formulation interaction component. Our simulation study compares the performance of four alternative mixed effects models: the FDA model, a three variance component model proposed by Ekbohm and Melander (EM), a random intercepts and slopes model (RIS) proposed by Patterson and Jones, and a simple model that contains only two variance components. The simple model fails (when not 'true') to provide adequate coverage and it accepts the hypothesis of equivalence too often. FDA and EM models are frequently indistinguishable and often provide the best performance with respect to coverage and probability of concluding BE. The RIS model concludes equivalence too often when both the within- and between-subject variance components differ between formulations. The FDA analysis model is recommended because it provides the most detail regarding components of variability and has a slight advantage over the EM model in confidence interval length.

Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin.

OBJECTIVE: This study compares the time-action profile of inhaled insulin (INH; Exubera) with that of subcutaneously injected insulin lispro (ILP) or regular human insulin (RHI) in healthy volunteers. RESEARCH DESIGN AND METHODS: In this open-label, randomized, three-way, crossover study, 17 healthy male volunteers were given each of the following treatments in random order: INH (6 mg), ILP (18 units), or RHI (18 units). Glucose infusion rates and serum insulin concentrations were monitored over 10 h. RESULTS: INH had a faster onset of action than both RHI and ILP, as indicated by shorter time to early half-maximal effect (32 vs. 48 and 41 min, respectively; P < 0.001 for IHN vs. RHI and P < 0.05 for IHN vs. ILP). Time to maximal effect was comparable between INH and ILP (143 vs. 137 min; NS) but was shorter for INH than RHI (193 min; P < 0.01). The maximal metabolic effect of INH was comparable with RHI but lower than ILP (8.7 vs. 9.8 vs. 11.2 mg . kg(-1) . min(-1), respectively; P < 0.01 for INH vs. ILP). The duration of action of INH, indicated by time to late half-maximal effect (387 min), was longer than ILP (313 min; P < 0.01) and comparable to RHI (415 min; NS). Total glucodynamic effect after inhalation of INH was comparable to both ILP and RHI (NS). Relative bioefficacy of INH was 10% versus RHI and 11% versus ILP. No drug-related adverse events were observed. CONCLUSIONS: INH had a faster onset of action than RHI or ILP and a duration of action longer than ILP and comparable to RHI. These characteristics suggest that inhaled insulin is suitable for prandial insulin supplementation in patients with diabetes.