Journal of Clinical Pharmacology最新文献

Polymorphisms in the drug transporter gene (ABCB1) may play a significant role in individualizing cyclosporine (CsA) and tacrolimus (Tac) dosage and subsequently the allograft outcome in renal transplant recipients. In total, 225 recipients on CsA and 75 on Tac-based immunosuppression regimen were recruited, and 6 common polymorphic sites in the ABCB1 gene were analyzed for association with dose-adjusted levels of CsA/Tac. Furthermore, association of ABCB1 single-nucleotide polymorphisms (SNPs) with allograft outcome was examined. GG and CC genotype patients at ABCB1 2677G>T and ABCB1 3435C>T were associated with lower dose-adjusted levels of CsA and Tac at 1 month (P = .057, P = .034), 3 months (P = .001, P = .015), and 6 months (P = .043) posttransplantation. Wild-type patients at 1236C>T (log P = .025) and 2677G>T (log P = .002) in CsA and 2677G>T (log P = .008) and 3435C>T (log P = .015) in Tac therapy patients demonstrated lower mean time to allograft rejection. No influence of ABCB1 haplotypes on CsA/Tac dose-adjusted levels was observed. Wild-type patients at ABCB1 2677G>T and 3435C>T were associated with lower dose-adjusted levels and thereby were at increased risk of allograft rejection because of under-immunosuppression in the early part of posttransplantation. Thus, genetic evaluation may be helpful to identify patients at risk for allograft rejection and also to individualize immunosuppressant dosing.

ABT-107 is a potent, selective α7 nicotinic receptor agonist under development for treatment of Alzheimer's disease and cognitive deficits associated with schizophrenia. The pharmacokinetics, safety, and tolerability of escalating single oral doses (1, 3, 10, 30, 60, 80, and 100 mg; double-blind, placebo-controlled, randomized, incomplete crossover design) and multiple oral doses (2, 6, and 15 mg once daily for 7 days; double-blind, placebo-controlled, randomized, parallel-group design) of ABT-107 were evaluated. Additionally, effect of food on ABT-107 pharmacokinetics (20-mg single dose) was evaluated using an open-label, 2-period, fasting and nonfasting, randomized, complete crossover design. ABT-107 exhibited nonlinear (more than dose-proportional) pharmacokinetics. ABT-107 half-life ranged from 7 to 10 hours, and steady state was achieved by day 6 of dosing. Food did not have a clinically meaningful effect on ABT-107 exposure. ABT-107 was safe and well tolerated over the tested dose range. The most frequently reported adverse events were nausea, headache, and tremor following single dosing and somnolence following multiple dosing. The pharmacokinetics, safety, and tolerability profiles of ABT-107 pose it as a good candidate for further development.

This nonrandomized, fixed-sequence, 2-period crossover study investigated potential pharmacokinetic interactions between the phosphodiesterase 4 inhibitor roflumilast, currently in clinical development for the treatment of chronic obstructive pulmonary disease, and the histamine 2 agonist cimetidine. Participants received roflumilast, 500 µg once daily, on days 1 and 13. Cimetidine, 400 mg twice daily, was administered from days 6 to 16. Pharmacokinetic analysis of roflumilast and its active metabolite roflumilast N-oxide was performed, and the ratio of geometric means for roflumilast alone and concomitantly with steady-state cimetidine was calculated. The effect of cimetidine on the total PDE4 inhibitory activity (tPDE4i; total exposure to roflumilast and roflumilast N-oxide) was also calculated. Coadministration of steady-state cimetidine increased mean tPDE4i of roflumilast and roflumilast N-oxide by about 47%. The maximum plasma concentration (C(max)) of roflumilast increased by about 46%, with no effect on C(max) of roflumilast N-oxide. The increase in tPDE4i of roflumilast and roflumilast N-oxide following coadministration with cimetidine was mainly due to the inhibitory effect of cimetidine on cytochrome P450 (CYP) isoenzymes CYP1A2, CYP3A, and CYP2C19. These moderate changes indicate that dose adjustment of roflumilast is not required when coadministered with a weak inhibitor of CYP1A2, CYP3A, and CYP2C19, such as cimetidine.

To determine acute analgesia by acetylsalicylic acid (ASA) when combined with pseudoephedrine (PSE) in patients with upper respiratory tract infection (URTI), we used the sore throat pain model to measure single-dose effects of ASA 500 mg/PSE 30 mg, ASA 1000 mg/PSE 60 mg, and acetaminophen (APAP) 1000 mg/PSE 60 mg (serving as a positive control). Under double-blind, randomized, placebo-controlled conditions, 640 adult patients with confirmed acute pharyngitis and rhinosinusitis associated with URTI rated throat pain intensity and relief at intervals over 6 hours. Efficacy was demonstrated for both doses of ASA/PSE compared with placebo for all end points, including total pain relief and summed pain intensity differences, beginning at 20 minutes on both scales (all P < .05), and the efficacy of APAP/PSE compared with placebo was confirmed (P < .01). Greater differences in pain relief and intensity were also demonstrated between the higher and lower doses of ASA/PSE (P < .05), in particular, among 329 patients with severe pain, as well as between ASA 1000 mg/PSE 60 mg and APAP 1000 mg/PSE 60 mg (P < .05). No serious adverse events were reported. This study demonstrates that ASA is a well-tolerated and effective analgesic in 500- and 1000-mg doses when combined with pseudoephedrine.

An extended-release trazodone HCl formulation, Trazodone Contramid OAD (TzCOAD), was developed as scored 150-mg and 300-mg caplets for once-daily administration. Dose proportionality of intact and bisected caplets (dose range, 75-375 mg) was evaluated in a single-dose, randomized, 5-way crossover study. Plasma trazodone and m-chlorophenylpiperazine (mCPP) levels were determined using a validated liquid chromatography-tandem mass spectroscopy method. Dose proportionality was assessed based on confidence intervals for logarithmically transformed, dose-normalized maximum plasma concentration (C(max)), area under the plasma concentration versus time data pairs (AUC(0-t)), and area under the curve from time 0 to infinity (AUC(0-∞)) in relation to the acceptance range of 80% to 125% (bioequivalence approach). The power method, combined with confidence interval criteria, was also used to assess proportionality. The conclusion of dose proportionality was generally supported using the bioequivalence approach. Based on the power model, values of the slope and corresponding 90% confidence interval for trazodone C(max), AUC(0-t), and AUC(0-∞) were 0.948 (0.899-0.997), 0.920 (0.875-0.964), and 0.913 (0.867-0.958), respectively. All were within the acceptance interval (0.861-1.139). Results for mCPP also fell within the acceptance interval. TzCOAD exhibits linear pharmacokinetics over doses ranging from 75 to 375 mg and maintains its controlled-release properties when the caplets are bisected along the score line.

Rasagiline is a selective, monoamine oxidase (MAO)-B inhibitor indicated for treatment of Parkinson's disease. This double-blind, placebo-controlled study determined the tyramine sensitivity factor (TSF) and degree of MAO-A inhibition (ie, reduction in plasma dihydroxyphenylglycol) in healthy volunteers who received phenelzine (15 mg, 3 times daily; positive control), selegiline (5 mg, twice daily), or rasagiline (1-6 mg, once daily) for 14 days or rasagiline 2 mg/d for 30 days. The selegiline/rasagiline groups were randomized to placebo or active drug. TSF was highest with phenelzine (17.3) and lowest with placebo (1.5). TSF with selegiline was 2.5. TSFs for rasagiline were as follows: 2.0 for 1 mg/d; 3.3 and 2.4 for 2 mg/d administered for 14 and 30 days, respectively; 4.5 for 4 mg/d; and 5.1 for 6 mg/d. Plasma dihydroxyphenylglycol concentrations suggested that rasagiline 1 mg/d had no effect, whereas rasagiline 2 mg/d had only minimal effect. In contrast, rasagiline 4 and 6 mg/d reduced dihydroxyphenylglycol to a degree approaching that achieved by the positive control phenelzine. Results demonstrate that rasagiline selectively inhibits MAO-B and is not associated with increased tyramine sensitivity at the indicated dose (1 mg/d). These data allowed removal of dietary tyramine restriction from rasagiline US labeling.

Understanding the dose-exposure-response relationship across the pediatric age spectrum from preterm and term newborns to infants, children, adolescents, and adults is a major challenge for clinicians, pharmaceutical companies, and regulatory agencies. Over the past 3 decades, clinical investigations of many drugs commonly used in pediatric therapeutics have provided valuable insights into age-associated differences in drug disposition and action. However, our understanding of the contribution of genetic variation to variability in drug disposition and response in children generally has lagged behind that of adults. This article proposes a systematic approach that can be used to assess the relative contributions of ontogeny and genetic variation for a given compound. Application of the strategy is illustrated using the current regulatory dilemma posed by the safety and effectiveness of over-the-counter cough and cold remedies as an example. The results of the analysis can be used to aid in the design of studies to yield maximally informative data in pediatric populations of different ages and developmental stages and thereby improve the efficiency of study design.

Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n = 392). A separate pooled analysis of 5 clinical studies in patients with hypertension (n = 2327) assessed the influence of gender and BMI on the effects of aliskiren on plasma renin activity and blood pressure. Area under the aliskiren plasma concentration-time curve (AUC(τ)) was 22% lower and the peak aliskiren plasma concentration (C(max)) was 24% lower in men than women (P < .05). BMI was not significantly correlated with AUC(τ) (r = 0.005; P = .917); AUC(τ) was negatively correlated with body weight (r = -0.235; P < .0001) and LBW (r = -0.295; P < .0001). Results were similar for C(max). Adjusting individual aliskiren AUC(τ) and C(max) values for overall mean body weight or LBW abolished gender differences. Based on r(2) values, LBW variation accounted for 8.9% of aliskiren AUC(τ) variation. In patients with hypertension, gender and BMI did not significantly influence the effects of aliskiren on plasma renin activity or blood pressure. It was concluded that lower systemic exposure to aliskiren in men versus women relates to differences in body weight; neither gender nor body weight has clinically relevant effects on the pharmacokinetics or pharmacodynamics of aliskiren.

This study investigated the relationship between pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA) in liver transplant patients receiving mycophenolate mofetil (MMF). Total and free plasma MPA concentrations were determined by high-performance liquid chromatography before MMF dose and at 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after dosing in 27 patients. The inhibitory capacity of serum MPA on proliferation of CEM cells was monitored at 0, 1, and 2 hours. The concentration of free MPA at 0, 1, and 2 hours (C(0h), C(1h), C(2h)) and the area under the concentration-time curve at 0 to 12 hours (AUC(0-12h)) of free MPA were significantly related to those of total MPA (P < .05). C(1h) and C(2h) of total and free MPA were conversely related with the rate of proliferation of CEM cells (P < .05). At 1 and 2 hours after an MMF dose, the percentage of CEM cell proliferation was below 40% in the majority of patients compared with the percentage before dosing. Thus, there was a significant relationship between total and free plasma MPA concentrations in liver transplant patients. After MMF dose, the inhibitory capacity of serum MPA on proliferation of CEM cells was enhanced significantly. This effect was related greatly to MPA concentrations.

This study investigates the potential benefits of antibiotics and N-acetylcysteine (NAC), a mucolytic agent, in patients who are candidates for endoscopic retrograde cholangiopancreatography (ERCP) due to partial bile duct obstruction. In total, 102 patients who had choledocholithiasis and choledochal dilatations by abdominal ultrasonography were included in the study. The patients were divided into placebo and NAC therapy groups. Physiological saline (equal volume with NAC solution) and ciprofloxacin (2 × 200 mg/d intravenously) were administered to the placebo group, and NAC (1800 mg/d intravenously) and ciprofloxacin (2 × 200 mg/d intravenously) were administered to the NAC group. In both groups, treatment protocols were administered for 7 days before ERCP. Total and direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), C-reactive protein (CRP), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), white blood cell (WBC) count, and neutrophil percent (NE%) levels were measured before the 7-day treatment protocol. The same measurements were also evaluated before ERCP. In the NAC group, the levels of ALP, GGT, WBC, CRP, and NE% decreased significantly (P < .001), whereas a significant decrease did not occur in the placebo group. The combined usage of NAC and ciprofloxacin can be an alternative therapeutic option until ERCP is performed in partial cholestatic patients.