Comparison of the exposure-response relationship of dapagliflozin in adult and paediatric patients with type 2 diabetes mellitus.

AIMS: To quantitatively compare the exposure-response relationship of dapagliflozin in adult and paediatric patients with type 2 diabetes mellitus (T2DM) and to assess the potential impact of covariate effects. METHODS: Data from three clinical studies of single-dose (2.5, 5 and 10 mg), orally administered dapagliflozin in adult (NCT00162305, NCT00538174) and paediatric (NCT01525238) patients with T2DM were analysed to examine the relationship between dapagliflozin exposure (area under concentration-time curve) and response [24-h urinary glucose excretion (UGE)] using a sigmoidal maximum effect model. Baseline fasting plasma glucose (FPG), estimated glomerular filtration rate (eGFR), baseline 24-h UGE, sex and race were evaluated as covariates. RESULTS: Data from 63 predominantly white or Asian (92.4%) adult and 20 paediatric (45.8% white; 45.8% black) patients were included. The model appeared robust, with predictions fitting well with observed data. Baseline eGFR, FPG and sex were significant covariates in both populations; race was a significant covariate in the paediatric population only. Model-predicted UGE response was higher in paediatric (47.4, 67.5 and 85.9 g/24 h for 2.5, 5 and 10 mg) than in adult (31.2, 43.5 and 54.3 g/24 h for 2.5, 5 and 10 mg) patients, which may be associated with the higher eGFR values in paediatric patients. CONCLUSIONS: After a single oral dose of dapagliflozin, adult and paediatric patients with T2DM had similar exposure-response relationships after accounting for significant covariates. These results support the planned dosage strategy for a phase III dapagliflozin safety and efficacy study in paediatric patients with T2DM, for whom treatment options are currently limited.

Pharmacokinetics and pharmacodynamics of dapagliflozin in children and adolescents with type 2 diabetes mellitus.

AIMS: To evaluate the pharmacokinetic (PK)/pharmacodynamic (PD) and safety profile of dapagliflozin in paediatric patients aged 10-17 years with type 2 diabetes mellitus (T2DM). METHODS: Patients were randomized to a single oral dose of dapagliflozin 2.5, 5 or 10 mg. The PK characteristics for individual patients were derived by non-compartmental methods. Urinary glucose excretion (UGE), fasting plasma glucose (FPG) and ease of swallowing were also evaluated. RESULTS: A total of 24 patients with a mean (range) body weight of 99.7 (61.5-169.5) kg received dapagliflozin. Dapagliflozin was rapidly absorbed after oral administration (median time to maximum plasma concentration ∼1.5 h) and systemic exposures to dapagliflozin and its 3-O-glucuronide metabolite appeared dose-proportional. The mean 24-h UGE increased in a dose-related manner (52.8, 62.4 and 89.0 g for the 2.5, 5 and 10 mg groups, respectively). Mean FPG concentrations were lower for all dose groups on day 2 (6.9, 6.2 and 6.8 mmol/l for 2.5, 5 and 10 mg groups, respectively) than they were predose on day 1 (9.5, 8.5 and 8.2 mmol/l for 2.5, 5 and 10 mg groups, respectively). Six patients (25%) experienced ≥1 adverse event (AE), however, there was no dose-related pattern. All AEs occurred only once and most were mild in intensity. Nearly all patients (n = 23; 95.8%) reported easy swallowing of the dapagliflozin tablets. CONCLUSIONS: Dapagliflozin was well tolerated in this paediatric population, with no significant safety findings. PK/PD characteristics were similar to those observed in adults with T2DM, thereby supporting the hypothesis that the same dapagliflozin dosage as that used in adults can be evaluated in future phase III paediatric studies.

Comparison of the pharmacokinetics and pharmacodynamics of dapagliflozin in patients with type 1 versus type 2 diabetes mellitus.

AIMS: To compare the pharmacokinetics and pharmacodynamics of dapagliflozin in patients with type 1 diabetes mellitus (T1DM) versus type 2 diabetes mellitus (T2DM) in order to explore the potential of dapagliflozin as add-on therapy to insulin in patients with T1DM. METHODS: Steady-state pharmacokinetics and pharmacodynamics of dapagliflozin (1-100 mg) were evaluated in a meta-analysis of patients with T1DM or T2DM. A model was constructed of the relationship between dapagliflozin systemic exposure and urinary glucose excretion (UGE) in patients with T1DM versus those with T2DM. RESULTS: Data were analysed from 160 patients (T1DM, n = 70; T2DM, n = 90). Dapagliflozin systemic exposure (maximum concentration and area under the curve) increased similarly in a dose-related manner in both patient populations. Dose-dependent increases in 24-h UGE were observed with dapagliflozin in both populations. Unadjusted results showed that with regard to UGE response, dapagliflozin was more potent in patients with T1DM {mean half-maximum effective concentration [EC50 ] = 2.72 ng/ml [95% confidence interval (CI) 1.14, 5.08]} than in patients with T2DM [EC50 = 12.2 ng/ml (95% CI 4.91, 21.1)]. After normalization for baseline fasting plasma glucose, estimated glomerular filtration rate and UGE, however, the UGE potency of dapagliflozin was similar between the two populations [T1DM: mean EC50 , 8.12 ng/ml (95% CI 2.95, 14.6); T2DM: mean EC50 , 7.75 ng/ml (95% CI 1.35, 18.1)]. CONCLUSIONS: Dapagliflozin pharmacokinetics and the predicted UGE dose exposure response to dapagliflozin were similar in patients with T1DM and those with T2DM and suggest that the dapagliflozin dosages currently used for the treatment of T2DM may provide benefit as add-on therapy to insulin in patients with T1DM.

Evaluation of 4ß-Hydroxycholesterol as a Clinical Biomarker of CYP3A4 Drug Interactions Using a Bayesian Mechanism-Based Pharmacometric Model.

A Bayesian mechanism-based pharmacokinetic/pharmacodynamic model of cytochrome P450 3A4 (CYP3A4) activity was developed based on a clinical study of the effects of ketoconazole and rifampin on midazolam exposure and plasma 4ß-hydroxycholesterol (4ßHC) concentrations. Simulations from the model demonstrated that the dynamic range of 4ßHC as a biomarker of CYP3A4 induction or inhibition was narrower than that of midazolam; an inhibitor that increases midazolam area under the curve by 20-fold may only result in a 20% decrease in 4ßHC after 14 days of dosing. Likewise, an inducer that elevates CYP3A4 activity by 1.2-fold would reduce the area under the curve of midazolam by 50% but would only increase 4ßHC levels by 20% after 14 days of dosing. Elevation in 4ßHC could be reliably detected with a twofold induction in CYP3A4 activity with study sample sizes (N ~ 6-20) typically used in early clinical development. Only a strong CYP3A4 inhibitor (e.g., ketoconazole) could be detected with similar sample sizes.

A Nonlinear Mixed Effects Pharmacokinetic Model for Dapagliflozin and Dapagliflozin 3-O-glucuronide in Renal or Hepatic Impairment.

Dapagliflozin is a sodium-glucose co-transporter 2 inhibitor in development for the treatment of type 2 diabetes mellitus. A semi-mechanistic population pharmacokinetic (PK) model was developed for dapagliflozin and its inactive metabolite dapagliflozin 3-O-glucuronide (D3OG) with emphasis on renal and hepatic contribution to dapagliflozin metabolism. Renal and hepatic impairment decreased the clearance of dapagliflozin to D3OG and the clearance of D3OG. The fraction of D3OG formed via the renal route decreased from 40-55% in subjects with normal renal function (creatinine clearance (CLcr) > 80 ml/min) to 10% in subjects with severe renal insufficiency (CLcr = 13 ml/min). The model-based simulations suggested that the increase of systemic exposure (AUCss) of dapagliflozin and D3OG was less than twofold in subjects with mild or moderate renal impairment. This population modeling analysis presents a useful approach to evaluate the impact of renal and hepatic function on the PK of dapagliflozin.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e42; doi:10.1038/psp.2013.20; advance online publication 8 May 2013.

Effects of rifampin and mefenamic acid on the pharmacokinetics and pharmacodynamics of dapagliflozin.

AIMS: Dapagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that decreases serum glucose by reducing renal glucose reabsorption, thereby promoting urinary glucose excretion. Dapagliflozin is primarily metabolized via the uridine diphosphate-glucuronosyltransferase (UGT)1A9 pathway to its major inactive metabolite, dapagliflozin 3-O-glucuronide. The aim of this study was to evaluate the potential for drug-drug interaction between dapagliflozin and two potential UGT1A9 modulators. METHODS: The results of two open-label, non-randomized, single-sequence studies are reported in which the effects of rifampin (a pleiotropic drug-metabolizing enzyme inducer; study 1) and mefenamic acid (a strong UGT1A9 inhibitor; study 2) were evaluated on the pharmacokinetics and pharmacodynamics (assessed by urinary glucose excretion [UGE]) of dapagliflozin in healthy subjects. In study 1, 14 subjects received single doses of dapagliflozin 10 mg alone and in the presence of rifampin 600 mg QD (6 days). In study 2, 16 subjects received single doses of dapagliflozin 10 mg alone and in the presence of mefenamic acid 250 mg q6h (5 days). RESULTS: Rifampin reduced total exposure (area under the concentration-time curve from time 0 to infinity [AUC0-inf]) to dapagliflozin by 22% and mefenamic acid increased dapagliflozin AUC0-inf by 51%. No clinically meaningful effect of rifampin or mefenamic acid on the pharmacokinetics of dapagliflozin or on dapagliflozin-mediated urinary glucose excretion was observed. CONCLUSION: Modest changes in dapagliflozin exposure were seen with rifampin and mefenamic acid with minor changes in UGE, none of which were considered clinically meaningful.

Lack of a pharmacokinetic drug-drug interaction between lithium and valproate when co-administered with aripiprazole.

WHAT IS KNOWN AND OBJECTIVE: The antipsychotic, aripiprazole, plus lithium or valproate demonstrates rapid and significant improvement in manic symptoms that is sustained over the long term. A previous report showed that therapeutic doses of either lithium or valproate had no clinically significant effects on the pharmacokinetics of aripiprazole. We aimed to determine the effects of co-administration of aripiprazole on the steady-state pharmacokinetics of lithium or valproate in healthy subjects. MATERIALS AND METHODS: Two similarly designed, open-label, single-sequence studies were conducted. Healthy subjects received daily oral doses of either lithium (450 mg every 12 h) or valproate (500 mg every 12 h) on Days 1-7. Following Day 7 was a 2-day washout period, and on Day 10, subjects began receiving oral doses of aripiprazole (10 mg once daily) for 2 days. Aripiprazole was then titrated from 10 to 20 mg once daily to establish tolerance of aripiprazole. On Day 14, the dose was escalated and subjects received aripiprazole 30 mg once daily for 13 days. Beginning on Day 20, subjects received lithium (450 mg every 12 h) or valproate (500 mg every 12 h) concomitantly with aripiprazole 30 mg once daily through Day 26. Serial blood samples for serum lithium or valproate concentration determination were collected for up to 12 h post-lithium or valproate administration on Days 7 and 26. RESULTS: The lithium study enrolled 32 healthy subjects (72% completed the study), and the valproate study enrolled 48 healthy subjects (58% completed the study). In both studies, the 90% confidence intervals for the ratios of population geometric means, with and without aripiprazole, were contained within 80% and 125% for both the C(max) and AUC(τ) , respectively. Furthermore, the addition of aripiprazole did not change the median T(max) of lithium or valproate (4 h). Thus, the addition of aripiprazole did not affect the steady-state pharmacokinetics of lithium or valproate. The majority of subjects (76·9% for aripiprazole plus lithium and 68·4% for aripiprazole plus valproate) reported adverse events, but this adverse event profile is consistent with what has been observed in other studies. WHAT IS NEW AND CONCLUSION: The addition of aripiprazole to either lithium or valproate had no clinically meaningful effects on the pharmacokinetics of either drug. In addition, co-administration of aripiprazole with lithium or valproate demonstrated no unexpected safety signals in healthy subjects.

Effect of saxagliptin on the pharmacokinetics of the active components of Ortho-Cyclen(®), a combined oral contraceptive containing ethinyl estradiol and norgestimate, in healthy women.

Saxagliptin (Onglyza™) is a dipeptidyl peptidase-4 (DPP4) inhibitor for treating type 2 diabetes mellitus. This open-label, randomized, two-way crossover study in 20 healthy female subjects investigated the effect of saxagliptin on the pharmacokinetics (PK) of the active components of a combined oral contraceptive (COC). Subjects received either COC (Ortho-Cyclen(®)) once daily (QD) for 21 days, then 5 mg saxagliptin QD + COC QD for 21 days, or vice versa. Coadministration of saxagliptin and COC did not alter the steady-state PK of the primary active oestrogen (ethinyl estradiol) or progestin (norelgestromin) COC components. The area under the concentration-time curve (AUC) and peak plasma concentration (Cmax) of an active metabolite of norelgestromin (norgestrel) were increased by 13 and 17%, respectively, a magnitude that was not considered clinically meaningful. Coadministration of saxagliptin and COC in this study was generally well-tolerated. Saxagliptin can be co-prescribed with an oestrogen/progestin combination for women taking oral contraceptive.

Effect of a high-fat meal on the pharmacokinetics of dapagliflozin, a selective SGLT2 inhibitor, in healthy subjects.

Dapagliflozin is a potent and selective inhibitor of sodium-glucose co-transporter type 2 that is being developed for the treatment of type 2 diabetes mellitus. This open-label, randomized, two-period, two-treatment (single doses of 10-mg dapagliflozin fasted or fed), crossover study was conducted to evaluate the effect of a high-fat meal on the pharmacokinetics of dapagliflozin in 14 healthy subjects. Compared to the fasted state, a high-fat meal decreased mean dapagliflozin maximum plasma concentrations (C(max) ) by 31%, increased the time to C(max) (T(max) ) by 1 h, but did not affect overall dapagliflozin systemic exposure [area under the plasma concentration-time curve (AUC)]. As the cumulative (daily) amount of glucose excreted in the urine induced by dapagliflozin is dependent upon dapagliflozin AUC, the effect of food on dapagliflozin C(max) is unlikely to have a clinically meaningful effect on dapagliflozin's efficacy. On the basis of these findings, dapagliflozin can be administered without regard to meals.

Saxagliptin, a potent, selective inhibitor of DPP-4, does not alter the pharmacokinetics of three oral antidiabetic drugs (metformin, glyburide or pioglitazone) in healthy subjects.

AIM: To evaluate the pharmacokinetic interactions of the potent, selective, dipeptidyl peptidase-4 inhibitor, saxagliptin, in combination with metformin, glyburide or pioglitazone. METHODS: To assess the effect of co-administration of saxagliptin with oral antidiabetic drugs (OADs) on the pharmacokinetics and tolerability of saxagliptin, 5-hydroxy saxagliptin, metformin, glyburide, pioglitazone and hydroxy-pioglitazone, analyses of variance were performed on maximum (peak) plasma drug concentration (C(max)), area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) [saxagliptin + metformin (study 1) and saxagliptin + glyburide (study 2)] and area under the concentration-time curve from time 0 to time t (AUC) [saxagliptin + pioglitazone (study 3)] for each analyte in the respective studies. Studies 1 and 2 were open-label, randomized, three-period, three-treatment, crossover studies, and study 3 was an open-label, non-randomized, sequential study in healthy subjects. RESULTS: Co-administration of saxagliptin with metformin, glyburide or pioglitazone did not result in clinically meaningful alterations in the pharmacokinetics of saxagliptin or its metabolite, 5-hydroxy saxagliptin. Following co-administration of saxagliptin, there were no clinically meaningful alterations in the pharmacokinetics of metformin, glyburide, pioglitazone or hydroxy-pioglitazone. Saxagliptin was generally safe and well tolerated when administered alone or in combination with metformin, glyburide or pioglitazone. CONCLUSIONS: Saxagliptin can be co-administered with metformin, glyburide or pioglitazone without a need for dose adjustment of either saxagliptin or these OADs.

Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus.

AIMS: Dapagliflozin, a selective, orally active inhibitor of the renal sodium-glucose co-transporter type 2 (SGLT2) is in development for the treatment of type 2 diabetes mellitus (T2DM). Here, the pharmacokinetics (PK) and pharmacodynamics (PD) of dapagliflozin were evaluated in healthy Japanese subjects and in Japanese subjects with T2DM. METHODS: Two studies were conducted: a single-ascending dose (SAD) study (2.5-50 mg) in 32 healthy subjects and a multiple-ascending dose (MAD) study (2.5-20 mg QD for 14 days) in 36 subjects with T2DM. Safety and tolerability were assessed in both studies. Single and multiple dose PK of dapagliflozin and its inactive major metabolite, dapagliflozin 3-O-glucuronide, and PD (urinary glucose parameters) were characterized. Plasma glucose parameters were assessed over 14 days in the MAD study. RESULTS: No serious adverse events or discontinuations due to adverse events occurred in either study. In healthy and T2DM subjects, dapagliflozin was rapidly absorbed with a time to maximum plasma concentration of 0.5-1.3 h. Systemic exposure of dapagliflozin and dapagliflozin 3-O-glucuronide, measured by maximum plasma concentration and area under the plasma concentration-time curve, increased proportional to dose. On a molar basis, systemic exposure to dapagliflozin 3-O-glucuronide was similar to parent dapagliflozin. There was a dose-related increase in the amount of glucose excreted in the urine (SAD and MAD), which was associated with dose-related decreases in plasma glucose parameters in subjects with T2DM (MAD). CONCLUSIONS: Dapagliflozin was well tolerated and showed predictable dose-proportional PK and PD parameters in both healthy and T2DM Japanese subjects.

Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium-glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects.

AIMS: Dapagliflozin increases urinary glucose excretion by selectively inhibiting renal sodium-glucose transporter 2, an insulin-independent mechanism of action that may be complementary to that of other oral antidiabetes drugs. The current studies assessed the potential for pharmacokinetic (PK) interaction between dapagliflozin and pioglitazone, metformin, glimepiride or sitagliptin in healthy subjects following single-dose administration. METHODS: In open-label, randomized, three-period, three-treatment crossover studies, 24 subjects received 50 mg dapagliflozin, 45 mg pioglitazone or the combination, while 18 subjects received 20 mg dapagliflozin, 1000 mg metformin or the combination. In an open-label, randomized, five-period, five-treatment, unbalanced crossover study, 18 subjects first received 20 mg dapagliflozin, 4 mg glimepiride or the combination, and afterward 100 mg sitagliptin or sitagliptin plus 20 mg dapagliflozin. Blood samples were taken over 72 h of each treatment period. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination:monotherapy being within the range of 0.80-1.25. RESULTS: Co-administration of dapagliflozin with pioglitazone, metformin, glimepiride or sitagliptin had no effect on dapagliflozin maximum plasma concentration (C(max) ) or area under the plasma concentration-time curve (AUC). Similarly, dapagliflozin did not affect the C(max) or AUC for the co-administered drug, except for slight extensions of the 90% CI for the ratio of geometric means for glimepiride AUC (upper limit 1.29) and pioglitazone C(max) (lower limit 0.75). All monotherapies and combination therapies were well tolerated. CONCLUSION: Dapagliflozin can be co-administered with pioglitazone, metformin, glimepiride or sitagliptin without dose adjustment of either drug.

The pharmacokinetics of standard antidepressants with aripiprazole as adjunctive therapy: studies in healthy subjects and in patients with major depressive disorder.

Possible effects of the atypical antipsychotic aripiprazole on the pharmacokinetics of standard antidepressant therapies (ADTs) were assessed in two open-label, non-randomised studies in healthy subjects (Studies 1 and 2) and two placebo-controlled studies in patients with major depressive disorder (MDD) (Studies 3 and 4). Healthy subjects received venlafaxine 75 mg/day (Study 1; N = 38) or escitalopram 10 mg/ day (Study 2; N = 25) with the addition of aripiprazole 10-20 mg/day (10 mg/day fixed dose in Study 2) for 14 days. Patients with MDD (N = 498; Studies 3 and 4) received escitalopram (10-20 mg/day), fluoxetine (20-40 mg/day), paroxetine controlled-release (37.5-50 mg/day), sertraline (100-150 mg/day) or venlafaxine extended-release (150-225 mg/day) for 8 weeks plus placebo. Incomplete responders were randomised (1:1) to placebo or adjunctive aripiprazole 2-20 mg/day. Blood samples were collected for pharmacokinetic analysis of ADTs. Plasma concentration-time data from Studies 3 and 4 were combined for statistical analysis. In healthy subjects, point estimates [90% CI] for the ratios of geometric means of C( max) (venlafaxine 1.148 [1.083-1.217]; escitalopram 1.04 [0.99-1.09]) and AUC(TAU) (venlafaxine 1.183 [1.130-1.238]; escitalopram 1.07 [1.04-1.11]) indicated no meaningful increase in ADT exposure in the presence of aripiprazole. In patients, point estimates for mean plasma concentration ratios indicated no substantial effect of aripiprazole on any ADT escitalopram 0.970 [0.911-1.033], fluoxetine 1.177 [1.049-1.321], paroxetine 0.730 [0.598-0.892], sertraline 0.958 [0.887-1.035] or venlafaxine 0.966 [0.887-1.051]. Aripiprazole had no meaningful effects on the pharmacokinetics of standard ADTs in either healthy subjects or patients with MDD.

Studies on the pharmacokinetics and metabolism of a gamma-secretase inhibitor BMS-299897, and exploratory investigation of CYP enzyme induction.

BMS-299897 is a gamma-secretase inhibitor that was effective in reducing amyloid beta-peptide (A beta) in transgenic mice and guinea pigs. Therefore, pharmacokinetic and drug metabolism studies were conducted in animals to support its clinical development. The compound appeared to have low to intermediate total body clearance and was orally bioavailable (24-100%). The oral absorption of BMS-299897 from solid dosage forms appeared to be dissolution rate-limited. BMS-299897 was distributed into extravascular space (V(ss) >or= 1.3 l kg(-1)), including brain (brain-to-plasma ratio = 0.13-0.50). BMS-299897 appeared to be a P-glycoprotein (P-gp) substrate as the brain-to-plasma ratio was two-fold higher in the mdr1a knockout mouse as compared with the wild-type. Apparent autoinduction by BMS-299897 was observed in murine and rat efficacy and toxicity studies. In vitro, BMS-299897 was a weaker inducer of cytochrome P450 3A4 (CYP3A4) and a weaker transactivator of human pregnane X receptor (hPXR) as compared with rifampicin. Induction of human UGT1A and UGT2B was evaluated in primary human hepatocytes, but the results were inconclusive. A low potential for autoinduction in humans was predicted at a clinical dose of 250 mg and the prediction was consistent with the findings from a clinical multiple-dose study with BMS-299897 in probable Alzheimer's patients.

Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects.

Dapagliflozin selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter-2 (SGLT2). It was developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug were evaluated in single-ascending-dose (SAD; 2.5-500 mg) and multiple-ascending-dose (MAD; 2.5-100 mg daily for 14 days) studies in healthy subjects. Dapagliflozin exhibited dose-proportional plasma concentrations with a half-life of approximately 17 h. The amount of glucosuria was also dose-dependent. Cumulative amounts of glucose excreted on day 1, relating to doses from 2.5-100 mg (MAD), ranged from 18 to 62 g; day 14 values were comparable to day 1 values, with no apparent changes in glycemic parameters. Doses of approximately 20-50 mg provided close-to-maximal SGLT2 inhibition for at least 24 h. Dapagliflozin demonstrates pharmacokinetic (PK) characteristics and dose-dependent glucosuria that are sustained over 24 h, which indicates that it is suitable for administration in once-daily doses and suggests that further investigation of its efficacy in T2DM patients is warranted.

A pharmacokinetic interaction study between butorphanol and sumatriptan nasal sprays in healthy subjects: importance of the timing of butorphanol administration.

Sumatriptan and butorphanol nasal sprays are commonly used agents for the management of migraine headaches. Under certain circumstances, these two agents may be administered closely in time. However, the possibility of a pharmacokinetic interaction and the safety of this regime have not been examined. In this crossover design study, 24 healthy subjects received the following four treatments, each separated by at least 7 days: 1 mg butorphanol (Stadol NS7); 20 mg sumatriptan (Imitrex Nasal Spray); or both formulations together with butorphanol administered either 1 or 30 min after sumatriptan. Serial plasma samples were collected for 24 h post-dose and analysed for butorphanol and/or sumatriptan by HPLC-MS/MS. Butorphanol plasma concentrations were reduced when it was administered 1 min (mean 28.6% decrease in AUC(0-infinity)), but not 30 min, after sumatriptan. The pharmacokinetics of sumatriptan were not substantially altered by butorphanol. The combination of nasally administered sumatriptan and butorphanol appeared safe. However, if butorphanol nasal spray is administered <30 min after sumatriptan nasal spray, the analgesic effect of butorphanol may be diminished due to reduced nasal absorption resulting from probable transient vasoconstriction of nasal blood vessels by sumatriptan.

A high-performance liquid chromatography assay with ultraviolet detection for olanzapine in human plasma and urine.

Olanzapine is a commonly used atypical antipsychotic medication for which therapeutic drug monitoring has been proposed as clinically useful. A sensitive method was developed for the determination of olanzapine concentrations in plasma and urine by high-performance liquid chromatography with low-wavelength ultraviolet absorption detection (214 nm). A single-step liquid-liquid extraction procedure using heptane-iso-amyl alcohol (97.5:2.5 v/v) was employed to recover olanzapine and the internal standard (a 2-ethylated olanzapine derivative) from the biological matrices which were adjusted to pH 10 with 1 M carbonate buffer. Detector response was linear from 1-5000 ng (r2>0.98). The limit of detection of the assay (signal:noise=3:1) and the lower limit of quantitation were 0.75 ng and 1 ng/ml of olanzapine, respectively. Interday variation for olanzapine 50 ng/ml in plasma and urine was 5.2% and 7.1% (n=5), respectively, and 9.5 and 12.3% at 1 ng/ml (n=5). Intraday variation for olanzapine 50 ng/ml in plasma and urine was 8.1% and 9.6% (n=15), respectively, and 14.2 and 17.1% at 1 ng/ml (n=15). The recoveries of olanzapine (50 ng/ml) and the internal standard were 83 +/- 6 and 92 +/- 6% in plasma, respectively, and 79 +/- 7 and 89 +/- 7% in urine, respectively. Accuracy was 96% and 93% at 50 and 1 ng/ml, respectively. The applicability of the assay was demonstrated by determining plasma concentrations of olanzapine in a healthy male volunteer for 48 h following a single oral dose of 5 mg olanzapine. This method is suitable for studying olanzapine disposition in single or multiple-dose pharmacokinetic studies.

Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate.

BACKGROUND: The pharmacokinetics and dynamics of methadone are characterized by high interindividual variability. This study aimed to examine a number of factors that may contribute to this variability. METHODS: Eight healthy drug-free women were administered 0.2 mg/kg of R,S-methadone orally. The concentrations of methadone's enantiomers in plasma and urine were monitored for 96 hours. Vital signs, blood biochemical parameters, and pupillary diameter were monitored frequently during this period. Cytochrome P450 3A (CYP3A) activity and alpha1-acid glycoprotein (alpha1-AGP) concentrations and phenotypes were determined. Pharmacokinetic and pharmacodynamic modeling was used to assess the influence of the above-mentioned covariables on methadone enantiomer disposition and actions. RESULTS: The pharmacokinetic profile of the active enantiomer of methadone, R -methadone, showed a relatively normal distribution with 38% to 90% of the interindividual variability in modeled pharmacokinetic parameters being explained by their individual variability in CYP3A activity, the cumulative amount of the main CYP3A4 metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine, excreted in the urine, the fraction unbound in plasma, and the alpha1-AGP orosomucoid 2 (ORM2) variant plasma concentration. S-Methadone showed an idiosyncratic distribution with largely unpredictable pharmacokinetics. Pupillary constriction response was highly variable between individuals. CONCLUSIONS: The disposition of the active enantiomer, R -methadone, can be predicted in part by CYP3A activity and protein binding to alpha1-AGP (ORM2), whereas S-methadone disposition is not well explained by the factors examined in this study. Central nervous system effects were difficult to interpret on the basis of plasma R-methadone pharmacokinetics.

A single dose of methadone inhibits cytochrome P-4503A activity in healthy volunteers as assessed by the urinary cortisol ratio.

AIMS: To examine the effect of a single oral dose of methadone on cytochrome P450 (CYP) 3A activity using the urinary 6beta-hydroxycortisol to cortisol ratio (UCR) as a marker of CYP3A activity. METHODS: A single oral dose (0.2 mg kg-1) of rac-methadone was administered to eight healthy female volunteers. Frequent blood samples and all urine over seven time periods was collected for 96 h following dosing. The UCR and the concentration of the major CYP3A metabolite of methadone, EDDP, were measured in urine. Methadone enantiomer concentrations were determined in plasma and urine. All quantifications were performed by validated high performance liquid chromatography assays. RESULTS: In all volunteers a significant decline of the UCR from immediately predose values was observed at the 4-8 and 8-12 h collection periods (P < 0.05, 95% CI for the differences: 0.4,16 and 0.6,16, respectively) with a return to immediately predose values after 2-3 days, suggesting methadone was an inhibitor of CYP3A. The UCR was found to be significantly correlated with the amount of EDDP excreted in the urine and with the area under the plasma concentration vs time profile for total (R + S) methadone, supporting in vitro data that CYP3A is primarily responsible for EDDP formation and has a significant influence on methadone disposition. CONCLUSIONS: Methadone appears to be a CYP3A inhibitor in vivo following a single oral dose and measurements of the urinary cortisol ratio appear to be a useful index to follow this inhibition.