A study of the pharmacokinetic interaction of istradefylline, a novel therapeutic for Parkinson's disease, and atorvastatin

The effect of steady-state istradefylline, an agent for Parkinson's disease with P-glycoprotein and CYP3A inhibitory activity, on the pharmacokinetics of atorvastatin and its metabolites was evaluated in healthy volunteers. A single 40-mg dose of atorvastatin was administered to 20 subjects. After a 4-day washout, subjects received a single 40-mg atorvastatin dose following 40 mg istradefylline (n=16) or placebo (n=4) daily for 14 days. Plasma samples collected for 96 hours after atorvastatin administration, alone and in combination, were analyzed for atorvastatin, orthohydroxy atorvastatin, and parahydroxy atorvastatin. Istradefylline increased atorvastatin C(max) (53%), AUC(0-infinity) (54%), and t((1/2)) (27%); and increased AUC(0-infinity) for orthohydroxy atorvastatin (18%), but had no significant effect on its C(max) or t((1/2)); and had minimal effect on parahydroxy atorvastatin AUC(0-infinity). The lack of inhibition by istradefylline on metabolite systemic exposure, combined with increased atorvastatin systemic exposure, suggests a predominant P-glycoprotein inhibitory effect of istradefylline.     

Dose proportionality and the effect of food on vildagliptin, a novel dipeptidyl peptidase IV inhibitor, in healthy volunteers

Vildagliptin is a potent and selective dipeptidyl peptidase IV inhibitor in development for the treatment of type 2 diabetes that improves glycemic control by enhancing alpha- and beta-cell responsiveness to glucose. Two open-label, single-dose, randomized, crossover studies in healthy subjects (ages 18-45 years) investigated the dose proportionality of vildagliptin pharmacokinetics (n = 20) and the effect of food (n = 24) on vildagliptin pharmacokinetics. There was a linear relationship (r(2) = 0.999) between vildagliptin doses of 25, 50, 100, and 200 mg and area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)). Dose proportionality was assessed using a statistical power model [X = alpha x (dose)(beta)]. The 90% confidence intervals of the proportionality coefficient, beta, for AUC(0-infinity) (1.15-1.19) and C(max) (1.04-1.14) indicated that deviations from dose proportionality were small (<7.7%). Doubling of dose led to 2.1- to 2.3-fold increases in AUC(0-infinity) and C(max) but no dose-dependent changes in time to reach C(max) or terminal elimination half-life. Administration of vildagliptin 100 mg following a high-fat meal decreased C(max) by 19% and AUC(0-infinity) by 10%. Vildagliptin displays approximately dose-proportional pharmacokinetics over the 25- to 200-mg dose range, and administration with food has no clinically relevant effect on vildagliptin pharmacokinetics.     

Multiple-dose pharmacokinetics, pharmacodynamics, and safety of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, in healthy male volunteers

Taranabant is a cannabinoid-1 receptor inverse agonist for the treatment of obesity. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of taranabant (5, 7.5, 10, or 25 mg once daily for 14 days) in 60 healthy male subjects. Taranabant was rapidly absorbed, with a median t(max) of 1.0 to 2.0 hours and a t(1/2) of approximately 74 to 104 hours. Moderate accumulation was observed in C(max) (1.18- to 1.40-fold) and AUC(0-24 h) (1.5- to 1.8-fold) over 14 days for the 5-, 7.5-, and 10-mg doses, with an accumulation half-life ranging from 15 to 21 hours. Steady state was reached after 13 days. After multiple-dose administration, plasma AUC(0-24 h) and C(max) of taranabant increased dose proportionally (5-10 mg) and increased somewhat less than dose proportionally for 25 mg. Taranabant was generally well tolerated up to doses of 10 mg and exhibited multiple-dose pharmacokinetics consistent with once-daily dosing.     

Pharmacokinetics of the antimalarial drug, AQ-13, in rats and cynomolgus macaques

The purpose of this study was to evaluate the bioavailability and pharmacokinetics of a new antimalarial drug, AQ-13, a structural analog of chloroquine (CQ) that is active against CQ-resistant Plasmodium species, in rats and cynomolgus macaques. Sprague-Dawley rats (n = 4/sex) were administered a single dose of AQ-13 intravenously (i.v.) (10 mg/kg) or orally (20 or 102 mg/kg). Blood and plasma samples were collected at several timepoints. AQ-13 achieved C(max) after oral administration at approximately 3 to 4 h and could be detected in blood for 2 to 5 days after oral administration. The ratio of area under the curve (AUC) values at the high and low dose for AQ-13 deviated from an expected ratio of 5.0, indicating nonlinear kinetics. A metabolite peak was noted in the chromatograms that was identified as monodesethyl AQ-13. Oral bioavailability of AQ-13 was good, approximately 70%. The pharmacokinetics of AQ-13 was also determined in cynomolgus macaques after single (i.v., 10 mg/kg; oral, 20 or 100 mg/kg) and multiple doses (oral loading dose of 50, 100, or 200 mg/kg on first day followed by oral maintenance dose of 25, 50, or 100 mg/kg, respectively, for 6 days). The AUC and C(max) values following single oral dose administration were not dose proportional; the C(max) value for AQ-13 was 15-fold higher following an oral dose of 100 mg/kg compared to 20 mg/kg. Monodesethyl AQ-13 was a significant metabolite formed by cynomolgus macaques and the corresponding C(max) values for this metabolite increased only 3.8-fold over the dose range, suggesting that the formation of monodesethyl AQ-13 is saturable in this species. The bioavailability of AQ-13 in cynomolgus macaques following oral administration was 23.8% for the 20-mg/kg group and 47.6% for the 100-mg/kg group. Following repeat dose administration, high concentrations of monodesethyl AQ-13 were observed in the blood by day 4, exceeding the AQ-13 blood concentrations through day 22. Saturation of metabolic pathways and reduced metabolite elimination after higher doses are suggested to play a key role in AQ-13 pharmacokinetics in macaques. In summary, the pharmacokinetic profile and metabolism of AQ-13 are very similar to that reported in the literature for chloroquine, suggesting that this new agent is a promising candidate for further development for the treatment of chloroquine-resistant malaria.     

The effects of ritonavir and lopinavir/ritonavir on the pharmacokinetics of a novel CCR5 antagonist, aplaviroc, in healthy subjects

AIMS: This study assessed the effects of the CYP3A inhibitors lopinavir/ritonavir (LPV/r) on the steady-state pharmacokinetics (PK) of aplaviroc (APL), a CYP3A4 substrate, in healthy subjects. METHODS: In Part 1, APL PK was determined in eight subjects who received a single oral 50-mg APL test dose with/without a single dose of 100 mg ritonavir (RTV). Part 2 was conducted as an open-label, single-sequence, three-period repeat dose study in a cohort of 24 subjects. Subjects received APL 400 mg every 12 h (b.i.d.) for 7 days (Period 1), LPV/r 400/100 mg b.i.d. for 14 days (Period 2) and APL 400 mg + LPV/r 400/100 mg b.i.d. for 7 days (Period 3). All doses were administered with a moderate fat meal. PK sampling occurred on day 7 of Periods 1 and 3 and day 14 of Period 2. RESULTS: In Part 1, a single RTV dose increased the APL AUC(0-infinity) by 2.1-fold [90% confidence interval (CI) 1.9, 2.4]. Repeat dose coadministration of APL with LPV/r increased APL exposures to a greater extent with the geometric least squares mean ratios (90% CI) being 7.7 (6.4, 9.3), 6.2 (4.8, 8.1) and 7.1 (5.6, 9.0) for the APL AUC, C(max), and C(min), respectively. No change in LPV AUC or C(max) and a small increase in RTV AUC and C(max) (28% and 32%) were observed. The combination of APL and LPV/r was well tolerated and adverse events were mild in severity with self-limiting gastrointestinal complaints most commonly reported. CONCLUSIONS: Coadministration of APL and LPV/r was well tolerated and resulted in significantly increased APL plasma concentrations.     

Pharmacokinetics of a novel agent, R667, in patients with emphysema

AIMS: To evaluate the pharmacokinetics of R667, a novel emphysema agent, in patients with moderate to severe emphysema. METHODS: Multiple-dose pharmacokinetics of R667 and its metabolites in emphysematous patients were studied in a multicentre, randomized, single-blind, and placebo-controlled trial. Four groups of 10 patients per group received placebo, 0.2, 0.5, or 1 mg R667 once a day for 14-16 days. On day 14 (+/-1), blood samples were taken at predose and 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 h after dosing. RESULTS: Pharmacokinetic analysis of the data indicated that the mean steady-state C(max) and AUC(0,tau) of R667 appeared to be dose proportional over the dose range of 0.2-1 mg when administered to emphysematous patients. Mean metabolite to R667 ratios for C(max) or AUC(0,tau) were, in general, similar across the dose range of 0.2-1 mg. CONCLUSIONS: The pharmacokinetics of R667 and its metabolites appeared to be similar for patients with emphysema and healthy volunteers. Multiple-dose administration of 0.2-1 mg of R667 for up to 16 days was well tolerated in patients with emphysema.     

Valproate reduces the glucuronidation of asenapine without affecting asenapine plasma concentrations

Asenapine is indicated for treatment of schizophrenia in the United States and acute treatment of manic or mixed episodes, as monotherapy (United States and European Union) or adjunct therapy (United States only), associated with bipolar I disorder. It is extensively metabolized; the 2 main metabolites are asenapine N-glucuronide and N-desmethyl-asenapine. The authors investigated the pharmacokinetic interactions between asenapine and valproate in an open-label, randomized, 2-way crossover study. Twenty-four healthy male volunteers received sublingual doses of asenapine 5 mg alone or under steady-state valproate (500 mg bid for 9 days). Blood samples collected until 72 hours postdosing were analyzed for asenapine, N-desmethyl-asenapine, and asenapine N-glucuronide. Compared with asenapine alone, valproate substantially reduced N-glucuronide formation (area under the curve from 0 to infinity [AUC(0-∞)] reduced 7.4-fold, maximum concentration [C(max)] reduced 6.6-fold) and moderately reduced N-desmethyl-asenapine formation (AUC(0-∞) reduced 30%, C(max) unchanged). Coadministration of valproate did not affect asenapine AUC(0-∞) and C(max) (confidence intervals for the ratios of asenapine AUC(0-∞) and C(max) were contained within the predefined 0.80-1.25 acceptance range). Low-dose valproate, although almost completely inhibiting glucuronidation of asenapine, did not affect the pharmacokinetics of asenapine itself, the entity primarily responsible for the pharmacologic effects of the drug.     

Effect of hepatic impairment on the multiple-dose pharmacokinetics of ranolazine sustained-release tablets

The effect of hepatic impairment on the pharmacokinetics of a sustained-release formulation of ranolazine and 3 major metabolites was investigated in an open-label, parallel-group study. Ranolazine (875-mg loading dose followed by 500 mg every 12 hours for a total of 4 maintenance doses) was administered to subjects with mild (n = 8) or moderate (n = 8) hepatic impairment and a matched control group of healthy volunteers (n = 16). Moderate, but not mild, hepatic impairment significantly increased ranolazine steady-state area under the concentration-time curve (AUC0-12) by 76% (P < .001) and maximum plasma concentration C(max) by 51% (P < .01). The AUC0-12 ratio (metabolite/ranolazine) decreased for all metabolites in parallel with the degree of hepatic impairment. AUC0-infinity for the CYP3A substrate midazolam administered as a single dose was significantly correlated with ranolazine AUC0-12 at steady state (r2 = .33, P < .001). Over the time interval studied, ranolazine was well tolerated in healthy subjects and hepatically impaired subjects.     

Pharmacokinetics of a guanfacine extended-release formulation in children and adolescents with attention-deficit-hyperactivity disorder

STUDY OBJECTIVE: To evaluate the single- and multiple-dose pharmacokinetics of an oral extended-release formulation of guanfacine in children and adolescents with a diagnosis of attention-deficit-hyperactivity disorder (ADHD). DESIGN: Phase I-II, open-label, dose-escalation study. SETTING: Clinical study center. PATIENTS: Fourteen children (aged 6-12 yrs) and 14 adolescents (aged 13-17 yrs) with ADHD. INTERVENTION: All patients received guanfacine as a single 2-mg dose on day 1. They received a daily dose of 2 mg on days 9-15, 3 mg on days 16-22, and 4 mg on days 23-29. MEASUREMENTS AND MAIN RESULTS: Blood samples, vital signs, and electrocardiograms (ECGs) were obtained before dosing on day 1 and at intervals over 24 hours, with repeat measurements on days 14 and 28. Guanfacine demonstrated linear pharmacokinetics. Mean plasma concentrations, peak exposure (C(max)), and total or 24-hour exposure (area under the concentration-time curve [AUC](0-infinity) or AUC(0-24), respectively) were as follows in children and adolescents, respectively: after a single 2-mg dose, AUC(0-infinity) was 65.2 +/- 23.9 ng x hour/ml and 47.3 +/- 13.7 ng x hour/ml and C(max) was 2.55 +/- 1.03 ng x ml and 1.69 +/- 0.43 ng/ml after multiple 2-mg doses, AUC(0-24) was 70.0 +/- 28.3 ng x hour/ml and 48.2 +/- 16.1 ng x hour/ml and C(max) was 4.39 +/- 1.66 ng/ml and 2.86 +/- 0.77 ng/ml; and after multiple 4-mg doses, AUC(0-24) was 162 +/- 116 ng x hour/ml and 117 +/- 28.4 ng x hour/ml and C(max) was 10.1 +/- 7.09 ng/ml and 7.01 +/- 1.53 ng/ml. After a single 2-mg dose, half-life was 14.4 +/- 2.39 hours in children and 17.9 +/- 5.77 hours in adolescents. The most frequent treatment-emergent adverse events were somnolence, insomnia, headache, blurred vision, and altered mood. Most were mild to moderate in severity, with the highest frequency associated with the 4-mg doses. Blood pressure, pulse, and ECG reading.hour/ml s were all within normal limits. CONCLUSION: Guanfacine extended-release formulation demonstrated linear pharmacokinetics. Plasma concentrations and concentration-related pharmacokinetic parameters were higher in children than in adolescents. These differences are likely due to heavier body weights in adolescents and young male subjects. No serious adverse events were reported.     

Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers

The pharmacokinetic interaction between sildenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, and ambrisentan, an ET(A)-selective, propanoic acid-based endothelin receptor antagonist (ERA), was studied in a 2-period crossover study in 19 healthy volunteers, with ambrisentan exposure (AUC(0-infinity)) and maximum plasma concentration (C(max)) determined over 24 hours for a 10-mg dose of ambrisentan alone and again after 7 days of sildenafil 20 mg 3 times daily. The AUC(0-infinity) and C(max) for sildenafil and N-desmethyl sildenafil (active metabolite) were determined over 24 hours for a 20-mg dose of sildenafil alone and again after 7 days of dosing with ambrisentan 10 mg once daily. There was no clinically relevant pharmacokinetic interaction between ambrisentan and sildenafil or N-desmethyl sildenafil. Ambrisentan C(max) was unchanged (96.3% [90% confidence interval: 86.0%-107.8%]), with a minor increase in AUC(0-infinity) (108.5% [102.6%-111.7%]) with sildenafil coadministration. Sildenafil C(max) was increased slightly (113.4% [99.6%-129.1%]), and AUC(0-infinity) was unchanged (98.7% [91.2%-110.5%]) with ambrisentan coadministration. N-desmethyl sildenafil was unaltered. Dose adjustment of either drug is not necessary compared with administration alone.     

Pharmacokinetics and safety of viramidine, a prodrug of ribavirin, in healthy volunteers

Ribavirin, part of the current first-line combination therapy for the treatment of chronic hepatitis C, has side effects-in particular, hemolytic anemia-that is frequently dose limiting. Based on animal studies, viramidine, a prodrug of ribavirin, is converted to ribavirin in the liver. Viramidine dosing yielded 50% higher ribavirin levels in the monkey liver but only half in plasma and red blood cells compared to ribavirin dosing. At the same dose, it also had a safer profile than ribavirin in a 28-day toxicity study in monkeys. The current study was carried out to evaluate the safety, tolerability, and pharmacokinetics of viramidine in healthy male volunteers (n = 8-18 on viramidine vs. 2 on placebo at each dose level) after oral dosing of viramidine at 200, 600, and 1200 mg. There were no serious adverse events, and most adverse events were mild. The percentages of treatment-emergent events judged to be possibly related to the study drug were 50% in the 1200-mg group, 26% in the 600-mg group, and none in the 200-mg group. Viramidine was orally absorbed and rapidly converted to ribavirin with a t(max) of 1.5 to 3.0 hours for both viramidine and ribavirin in plasma. There was dose proportionality in plasma AUC(0-168 h) and C(max) for viramidine and in plasma AUC(0-168 h) for ribavirin. Plasma AUC(0-168 h) for ribavirin was two to four times higher than plasma AUC(0-168 h) for viramidine, indicating that viramidine is extensively metabolized to ribavirin and is a prodrug of ribavirin in man. Amounts of viramidine and ribavirin excreted in the urine were small (2%-5% of dose), indicating that the main route of elimination for both viramidine and ribavirin is metabolism. Both viramidine and ribavirin were excreted into urine through the mechanism of glomerular filtration. In addition, an evaluation of the effect of a high-fat meal on the pharmacokinetics of viramidine and ribavirin after oral dosing of viramidine at 600 mg was conducted in healthy male volunteers (n = 33-34) in a crossover study design. A high-fat meal increased viramidine plasma AUC(0-168 h) by 44% and C(max) by 20%. It also increased ribavirin plasma AUC(0-168 h) by 19% and C(max) by 43%. The clinical relevance of these increases is unknown.     

Comparison of two endogenous biomarkers of CYP3A4 activity in a drug–drug interaction study between midostaurin and rifampicin

Purpose

Midostaurin, a multitargeted tyrosine kinase inhibitor, is primarily metabolized by CYP3A4. This midostaurin drug–drug interaction study assessed the dynamic response and clinical usefulness of urinary 6β-hydroxycortisol to cortisol ratio (6βCR) and plasma 4β-hydroxycholesterol (4βHC) for monitoring CYP3A4 activity in the presence or absence of rifampicin, a strong CYP3A4 inducer.

Methods

Forty healthy adults were randomized into groups for either placebo or treatment with rifampicin 600 mg QD for 14 days. All participants received midostaurin 50 mg on day 9. Midostaurin plasma pharmacokinetic parameters were assessed. Urinary 6βCR and plasma 4βHC levels were measured on days 1, 9, 11, and 15.

Results

Both markers remained stable over time in the control group and increased significantly in the rifampicin group. In the rifampicin group, the median increases (vs day 1) on days 9, 11, and 15 were 4.1-, 5.2-, and 4.7-fold, respectively, for 6βCR and 3.4-, 4.1-, and 4.7-fold, respectively, for 4βHC. Inter- and intrasubject variabilities in the control group were 45.6 % and 30.5 %, respectively, for 6βCR, and 33.8 % and 7.5 %, respectively, for 4βHC. Baseline midostaurin area under the concentration–time curve (AUC) correlated with 4βHC levels (ρ?=??0.72; P?=?.003), but not with 6βCR (ρ?=?0.0925; P?=?.6981).

Conclusions

Both 6βCR and 4βHC levels showed a good dynamic response range upon strong CYP3A4 induction with rifampicin. Because of lower inter- and intrasubject variability, 4βHC appeared more reliable and better predictive of CYP3A4 activity compared with 6βCR. The data from our study further support the clinical utility of these biomarkers.     

Lack of dose-dependent effects of itraconazole on the pharmacokinetic interaction with fexofenadine.

The aim of this study was to determine the inhibitory effect of itraconazole at different coadministered doses on fexofenadine pharmacokinetics. In a randomized four-phase crossover study, 11 healthy volunteers were administered a 60-mg fexofenadine hydrochloride tablet alone on one occasion (control phase) and with three different doses of 50, 100, and 200 mg of itraconazole simultaneously on the other three occasions (itraconazole phase). Although the elimination half-life and the renal clearance of fexofenadine remained relatively constant, a single administration of itraconazole with fexofenadine significantly increased mean area under the plasma concentration-time curve (AUC(0-infinity)) of fexofenadine (1701/3554, 4308, and 4107 ng h/ml for control; 50 mg, 100 mg, and 200 mg of itraconazole, respectively). Although mean itraconazole AUC(0-48) from 50 mg to 200 mg increased dose dependently from 214 to 772 ng h/ml (p = 0.003), no significant difference was noted in the three parameters, AUC (p = 0.423), C(max) (p = 0.636), and renal clearance (p = 0.495), of fexofenadine among the three doses of itraconazole. Itraconazole exposure at a lower dose (50 mg) compared with the clinical dose (200 mg once or twice daily) had the maximal effect on fexofenadine pharmacokinetics, even though itraconazole plasma concentrations gradually increased after higher doses. These findings suggest that the interaction may occur at the gut wall before reaching the portal vein circulation, and the inhibitory effect must be saturated by substantial local concentrations of itraconazole in the gut lumen after 50-mg dosing.     

Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide

Effects of single and multiple doses of oral ketoconazole on roflumilast and its active metabolite, roflumilast N-oxide, were investigated in healthy subjects. In study 1, subjects (n = 26) received oral roflumilast 500 microg once daily for 11 days and a concomitant 200-mg single dose of ketoconazole on day 11. In study 2, subjects (n = 16) received oral roflumilast 500 microg on days 1 and 11 and a repeated dose of ketoconazole 200 mg twice daily from days 8 to 20. Coadministration of single-dose ketoconazole with steady-state roflumilast increased the AUC of roflumilast by 34%; C(max) was unchanged. For roflumilast N-oxide, AUC and C(max) decreased by 12% and 20%, respectively. Repeated doses of ketoconazole increased the AUC and C(max) of roflumilast by 99% and 23%, respectively; for roflumilast N-oxide, AUC was unchanged, and C(max) decreased by 38%. No clinically relevant adverse events were observed. Coadministration of ketoconazole and roflumilast does not require dose adjustment of roflumilast.     

Effect of R667, a novel emphysema agent, on the pharmacokinetics of midazolam in healthy men

The purpose of this study was to investigate the potential for a CYP3A4-mediated drug interaction between R667 and midazolam (MDZ) in healthy subjects. R667 is metabolized by CYP3A4 and therefore may interact with CYP3A4 substrates. In the present study, 18 healthy male subjects received a single 15-mg oral dose of MDZ with and without R667 coadministration. Serial blood samples were collected predose and up to 24 hours after each MDZ dose for pharmacokinetic (PK) evaluation. The PK parameters for MDZ, R667, and metabolites were estimated using noncompartmental methods. MDZ exposure was very similar in the presence and absence of R667 (C(max) = 50.8 vs 46.2 ng/mL; AUC(0-last) = 215 vs 216 ng.h/mL; AUC(0-last) ratio = 0.26 vs 0.26, respectively). R667 exposure was not affected by midazolam coadministration as compared with historical data. Based on the results of this study, no significant pharmacokinetic interaction should be anticipated between R667 and CYP3A4 substrates.     

Open-label steady-state pharmacokinetic drug interaction study on co-administered quetiapine fumarate and divalproex sodium in patients with schizophrenia, schizoaffective disorder, or bipolar disorder

OBJECTIVE: To determine whether there is a pharmacokinetic drug interaction between quetiapine fumarate and divalproex sodium. METHODS: The pharmacokinetics and short-term tolerability and safety of coadministered quetiapine and divalproex were examined in adults with schizophrenia/schizoaffective disorder (Cohort A) or bipolar disorder (Cohort B) in an open-label, parallel, 2-cohort drug-interaction study conducted at three centers in the United States. Cohort A was administered quetiapine (150 mg bid) prospectively for 13 days, with divalproex (500 mg bid) added on days 6-13. Cohort B was administered divalproex (500 mg bid) for 16 days, with quetiapine (150 mg bid) added on days 9-16. Quetiapine and valproic acid plasma concentration-time data over a 12-h steady-state dosing interval were used to determine C(max), T(max), C(min), area under the plasma concentration-time curve (AUC(tau)), and oral clearance (CL/F). RESULTS: In Cohort A (n = 18), addition of divalproex did increase the C(max) of quetiapine by 17% but did not change AUC(tau). In Cohort B (n = 15), addition of quetiapine decreased both total valproic acid C(max) and AUC(tau) by 11%. No differences were observed in adverse events (AEs) with either quetiapine or divalproex monotherapy or their combination. CONCLUSION: Combination therapy with quetiapine (150 mg bid) and divalproex (500 mg bid) resulted in small and statistically non-significant pharmacokinetic changes.     

Pharmacokinetics of montelukast in asthmatic patients 6 to 24 months old

Montelukast is a cysteinyl leukotriene receptor antagonist approved for the treatment of asthma for those ages 1 year old to adult. The purpose of this study was to evaluate the pharmacokinetic comparability of a 4-mg dose of montelukast oral granules in patients > or = 6 to < 24 months old to the 10-mg approved dose in adults. This was an open-label study in 32 patients. Population pharmacokinetic parameters included estimates of AUC(pop), C(max), and t(max). Results were compared with estimates from adults (10-mg film-coated tablet [FCT]). Dose selection criteria were for the 95% confidence interval (CI) for the AUC(pop) estimate ratio (pediatric/adult 10 mg FCT) to be within comparability bounds of (0.5, 2.00). The AUC(pop) ratio and the 95% CI for children compared with adults were within the predefined comparability bounds. Observed plasma concentrations were also similar. Based on systemic exposure of montelukast, a 4-mg dose of montelukast appears appropriate for children as young as 6 months of age.     

Inhibitory effect of troleandomycin on the metabolism of omeprazole is CYP2C19 genotype-dependent

1. Eighteen healthy CYP2C19 genotyped male subjects were administered a 20-mg oral dose of omeprazole (OP) alone or received troleandomycin (TAO) 500 mg daily for 2 days before the dose of OP was administered. Blood samples were obtained and OP 5-hydroxyomeprazole (5-OH-OP) and OP sulfone in plasma were determined by reversed-phase HPLC. 2. The mean C(max), AUC and CL for OP in poor metabolizers (PMs) were greater with TAO than without TAO. The C(max) and AUC of 5-OH-OP in PMs were significantly (p < 0.05) less with TAO than without TAO. The differences in 5-OH-OP between heterozygous extensive metabolizers (EMs) with TAO versus without TAO were similar to those observed in PMs, except for the AUC. However, in homozygous EMs, there were no statistical differences for the effect of TAO. 3. The effect of TAO on the metabolism of OP and its two principal metabolites differs in different genotype groups of CYP2C19. CYP3A4 not only plays a dominant role in the formation of OP sulfone, but also it contributes to the 5-hydroxylation of OP. Both CYP2C19 and CYP3A contribute to the further elimination of 5-OH-OP and OP sulfone.     

Inhibitory effect of troleandomycin on the metabolism of omeprazole is CYP2C19 genotype-dependent

1. Eighteen healthy CYP2C19 genotyped male subjects were administered a 20-mg oral dose of omeprazole (OP) alone or received troleandomycin (TAO) 500 mg daily for 2 days before the dose of OP was administered. Blood samples were obtained and OP 5-hydroxyomeprazole (5-OH-OP) and OP sulfone in plasma were determined by reversed-phase HPLC. 2. The mean C max, AUC and CL for OP in poor metabolizers (PMs) were greater with TAO than without TAO. The C max and AUC of 5-OH-OP in PMs were significantly (p < 0.05) less with TAO than without TAO. The differences in 5-OH-OP between heterozygous extensive metabolizers (EMs) with TAO versus without TAO were similar to those observed in PMs, except for the AUC. However, in homozygous EMs, there were no statistical differences for the effect of TAO. 3. The effect of TAO on the metabolism of OP and its two principal metabolites differs in different genotype groups of CYP2C19. CYP3A4 not only plays a dominant role in the formation of OP sulfone, but also it contributes to the 5-hydroxylation of OP. Both CYP2C19 and CYP3A contribute to the further elimination of 5-OH-OP and OP sulfone.