Clinical pharmacokinetic and pharmacodynamic profile of midazolam nasal spray.

The benzodiazepine midazolam (MDZ) is commonly used as first-line treatment in patients with acute seizures. This review summarizes the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MDZ nasal spray (MDZ-NS), which can be administered by non-health care providers in the outpatient, ambulatory setting. Intranasal administration leads to rapid (tmax 9.0-21.5 min), consistent, and extensive absorption of MDZ, with fast distribution to the central nervous system (CNS), as demonstrated by the onset of sedation within 10 min after administration and the occurrence of peak psychomotor impairment at approximately 17-120 min after administration. Rapid plasma clearance of MDZ and its active metabolite 1-OH-MDZ (t½ 3.6-8.1 h) results in a return to baseline alertness and psychomotor functionality by approximately 240 min post dose. The lack of first-pass metabolism reduces the potential for drug-drug interactions compared with oral dosing. Age (≥ 12 years), sex, race, body weight, body mass index, normal to moderately impaired renal function, and concomitant administration of cytochrome P450 (CYP)3A-inducing drugs are not considered important factors for MDZ-NS dosing. However, coadministration of MDZ-NS with moderate or strong CYP3A4 inhibitors should be avoided, and MDZ-NS should be used with caution when coadministered with mild CYP3A4 inhibitors, as these may result in prolonged MDZ effects owing to a decrease in plasma clearance. Taken together, the PK and PD properties of MDZ-NS, with a short tmax that translates into rapid CNS PD effects of sedation and psychomotor impairment, demonstrate rapid CNS penetration and onset of action, supporting its use for acute treatment of seizure clusters.

Phase I study assessing the safety, tolerability, and pharmacokinetics of avibactam and ceftazidime-avibactam in healthy Japanese volunteers.

Avibactam is a novel non-ß-lactam ß-lactamase inhibitor that has been shown to restore the in vitro activity of ceftazidime against pathogens producing Ambler class A, C, and some class D ß-lactamases. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of avibactam alone or with ceftazidime in healthy Japanese subjects. In this Phase I, double-blind study (NCT01291602), 16 healthy Japanese males, mean age 28.8 years, were randomized in a 2:2:1 ratio to receive avibactam 500 mg (n = 6), ceftazidime 2000 mg plus avibactam 500 mg (n = 7), or placebo (n = 3), each administered as a 100 ml intravenous infusion over 2 h, once on Day 1, every 8 h on Days 3-6, and once on Day 7. There were no deaths or serious adverse events. Nine treatment-emergent adverse events were reported in three subjects in the avibactam group - including one elevation in transaminase levels, and three vital signs events (tachycardia, palpitations, and orthostatic hypotension) - and one in the ceftazidime-avibactam group. All events were considered mild. After single or multiple dosing, plasma concentrations of avibactam and ceftazidime declined in a multi-exponential manner. No plasma concentration accumulation was observed, and the majority of avibactam was excreted unchanged in urine within 24 h. No clinically relevant changes in intestinal bacterial flora were observed. In conclusion, avibactam alone and ceftazidime-avibactam were generally well tolerated in healthy male Japanese subjects, and avibactam pharmacokinetics were comparable whether administered alone or in combination with ceftazidime.

Safety and pharmacokinetics of daclizumab in pediatric renal transplant recipients.

This study examined the safety and pharmacokinetics/pharmacodynamics of daclizumab in combination with mycophenolate mofetil (or azathioprine), corticosteroids, and cyclosporine or tacrolimus, in 61 pediatric renal allograft recipients in three age groups: less than or equal to five yr (n = 18), 6-12 yr (n = 18), and 13-17 yr (n = 25). The dosing regimen was daclizumab 1.0 mg/kg before transplantation, followed by four biweekly doses. The pharmacokinetics of daclizumab were described using NONMEM software. Median (range) estimated trough daclizumab levels achieved on day 56 (before dose 5) were 3.88 microg/mL (2.48-8.78), 4.54 microg/mL (1.79-18.7), and 4.94 microg/mL (0.05-10.6) in the less than or equal to five yr (n = 15), 6-12 yr (n = 17), and 13-17 yr (n = 22) age groups, respectively. Steady-state median (range) daclizumab exposures were 2040 mg x h/mL (1585-3778), 2757 mg x h/mL (1873-3494) and 3297 mg x h/mL (1705-6453), respectively. Saturation of the IL-2R occurred rapidly and was maintained for greater than or equal to three months after transplantation. Daclizumab was generally well-tolerated with no acute allergic or anaphylactic reactions, deaths or malignancies during the study. The proportion of patients who developed acute rejection at six and 12 months was 8.5% and 16.7%, respectively. This study shows that adding daclizumab at 1 mg/kg to standard immunosuppressive therapy provides safe and effective IL-2R blockade.

Pharmacokinetics, safety, and efficacy of mycophenolate mofetil in combination with sirolimus or ciclosporin in renal transplant patients.

AIMS: To compare the pharmacokinetics of mycophenolic acid (MPA) and its metabolite (MPAG) when mycophenolate mofetil (MMF) is administered in combination with sirolimus or ciclosporin (CsA) in renal allograft recipients. Safety and efficacy (biopsy-proven acute rejection (BPAR)) were also assessed. METHODS: Patients (n = 45) were randomized 2 : 1 to receive treatment with sirolimus (n = 30; dosed to maintain trough concentrations of 10-25 ng ml(-1) until week 8, and then 8-15 ng ml(-1) thereafter) or CsA (n = 15; administered as per centre practice) both in combination with daclizumab, oral MMF and corticosteroids. Pharmacokinetic assessments were performed at day 7, week 4, and months 3 and 6 post-transplant. The primary endpoint was the AUC(0,12 h) for MPA and MPAG. The pharmacokinetics of sirolimus were also assessed. RESULTS: MPA exposure was 39-50% lower (month 6 mean AUC(0,12 h) (95%CI): 40.4 (33.8, 47.0) vs. 68.5 (54.9, 82.0) microg ml(-1) h) and MPAG exposure was 25-52% higher (722 (607, 838) vs. 485 (402, 569) microg ml(-1) h at month 6) in the presence of CsA compared with sirolimus across visits. BPAR was 40.0% with sirolimus and 13.3% with CsA. The incidence of hypertension, tremors and hirsutism was higher with CsA than with sirolimus, while the incidence of diarrhoea, hyperlipidaemia and impaired wound closure was higher with sirolimus. No deaths, malignancies or graft losses were reported. CONCLUSIONS: Co-administration of sirolimus with MMF led to greater MPA exposure, but lower MPAG exposure, than co-administration with CsA. As rejection rates were higher in the absence of CsA, further study of calcineurin inhibitor-free regimens is required before general recommendations can be made.

Assessment of type I error rates for the statistical sub-model in NONMEM.

The aim of this study was to assess the type I error rate when applying the likelihood ratio (LR) test, for components of the statistical sub-model in NONMEM. Data were simulated from a pharmacokinetic one compartment intravenous bolus model. Two models were fitted to the data, the simulation model and a model containing one additional parameter, and the difference in objective function values between models was calculated. The additional parameter was either (i) a covariate effect on the interindividual variability in CL or V, (ii) a covariate effect on the residual error variability, (iii) a covariance term between CL and V, or (iv) interindividual variability in V. Factors in the simulation conditions (number of individuals and samples per individual, interindividual and residual error magnitude, residual error model) were varied systematically to assess their potential influence on the type I error rate. Different estimation methods within NONMEM were tried. When the first-order conditional estimation method with interaction (FOCE INTER) was used the estimated type I error rates for inclusion of a covariate effect (i) on the interindividual variability, or (ii) on the residual error variability, were in agreement with the type I error rate expected under the assumption that the model approximations made by the estimation method are negligible. When the residual error variability was increased, the type I error rates for (iii) inclusion of covariance between etaCL-etaV were inflated if the underlying residual distribution was lognormal, or if a normal distribution was combined with too little information in the data (too few samples per subject or sampling at uninformative time-points). For inclusion of (iv) etaV, the type I error rates were affected by the underlying residual error distribution; with a normal distribution the estimated type I error rates were close to the expected, while if a non-normal distribution was used the type I errors rates increased with increasing residual variability. When the first-order (FO) estimation method was used the estimated type I error rates were higher than the expected in most situations. For the FOCE INTER method, but not the FO method, the LR test is appropriate when the underlying assumptions of normality of residuals, and of enough information in the data, hold true. Deviations from these assumptions may lead to inflated type I error rates.