Significant Pharmacokinetic Interactions Research Articles

Pharmacodynamic and Pharmacokinetic Interaction Studies of Loreclezole with Felbamate, Lamotrigine, Topiramate, and Oxcarbazepine in the Mouse Maximal Electroshock Seizure Model

The study investigated the types of interactions between loreclezole (LCZ) and a variety of newly licensed antiepileptic drugs (AEDs) with different mechanisms of actions [felbamate (FBM), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC)] by isobolographic analysis. Anticonvulsant and adverse-effect profiles of combinations of LCZ with other AEDs at fixed ratios of 1:3, 1:1, and 3:1 were investigated in the maximal electroshock (MES)-induced seizures and the chimney test (as a measure of motor impairment) in mice so as to identify optimal combinations. Protective indices (PIs) and benefit indices (BIs) were calculated so that a ranking in relation to advantageous combinations could be established. With isobolography, it was observed that the combination of LCZ and TPM, at the fixed ratios of 1:1 and 3:1, was supraadditive (synergistic; p < 0.05), whereas LCZ with TPM at the fixed ratio of 1:3 and LCZ combined with LTG, FBM, or OXC at the fixed ratios of 1:3, 1:1, and 3:1 were associated with additive interactions. Moreover, the isobolographic analysis in the chimney test revealed that only one combination tested (LCZ and TPM at the fixed ratio of 1:1) was subadditive (antagonistic; p < 0.05), whereas the remaining combinations of LCZ with LTG, FBM, or OXC (at the fixed ratios of 1:3, 1:1, and 3:1) barely displayed additivity. However, these combinations were associated with significant pharmacokinetic interactions, in that LCZ increased brain TPM (94%), OXC (21%), FBM (46%), and LTG (8%) concentrations. In addition, brain LCZ concentrations were decreased by TPM (26%), OXC (37%), LTG (42%), and FBM (19%). None of the examined combinations between LCZ and TPM, OXC, LTG, and FBM altered long-term memory in the step-through passive-avoidance task. LCZ plus TPM appears to be a particularly favorable combination, based on the MES test and the chimney test. LCZ and OXC also is a favorable combination. However, these conclusions are confounded by the fact that LCZ is associated with significant pharmacokinetic interactions.

Population pharmacokinetic modeling of the interaction between the P-glycoprotein inhibitor PSC-833 and mitoxantrone in pediatric leukemia patients

Aim PSC 833 is a safer and more potent P-glycoprotein inhibitor than its parent drug, cyclosporine. It has significant pharmacokinetic (PK) interactions with common chemotherapeutic drugs. To examine and quantify this interaction, we modeled the change in clearance of the antileukemic drug mitoxantrone (MTX) upon the co-administration of PSC. Methods PSC and MTX PK data on 14 patients were obtained from a Phase I clinical trial with pediatric patients having acute leukemia. On day 1, patients received MTX as an IV infusion of 10mg/m2 over 15 min. From day 2 to 5, the dose was halved and PSC was given as a 2mg/kg loading dose over 2h along with a continuous infusion at varying dose levels (8, 10, 12.5 and 15 mg/kg/day) for 5 days. Both the PSC and MTX data were fit to 2-compartment models. The effect of PSC on MTX clearance was modeled as follows: CLMTX= CL0+(CL1−CL0) * PSC/(PSC+EC50) where CL0 is the baseline clearance, CL1 is the asymptotic value of CL (when PSC ∞) for large concentrations of PSC. Results The population parameter estimates (%CV) obtained using NONMEM were: CLPSC=1.2 L/h (58%), V1PSC=2.4 L, V2PSC=41.5 L (473%) CL0= 16.5 L/h (47%), CL1=6.12 L/h (64%), EC50=0.5 mg/L, V1MTX=23.2 L, V2MTX=98.5 L. Conclusions We successfully modeled PSC and MTX PK and their interaction in pediatric leukemia patients. Our model allows us to estimate CLMTX at different PSC concentrations. PSC has a large effect on CLMTX (73% reduction). Clinical Pharmacology & Therapeutics (2005) 77, P32–P32; doi: 10.1016/j.clpt.2004.12.013

Combined administration of duloxetine (DU) and lorazepam (LO): A pharmacokinetic (PK) and pharmacodynamic (PD) study

Background/Aims DU is a relatively balanced and potent dual inhibitor of norepinephrine and serotonin transporters, indicated for depression and targeted for female stress urinary incontinence. To assess possible DU-LO interaction, a randomized, double-blind, two-period, crossover study was conducted in 16 healthy subjects. Methods DU (60mg BID) or placebo was given for 8 days; LO (2 mg BID) was given from Day 5 to Day 8. PK profiles (DU and LO) were obtained on Day 4 (DU alone) and Day 8 (DU+ LO or LO alone). Critical Flicker Fusion Threshold (CFFT), Multiple Choice Reaction Time (MCRT), Digit Symbol Substitution Test (DSST) and the Bond and Lader Scale (BL) were administered at regular intervals on Days 4, 5 and 8. Immediate and Delayed Word Recall tests were performed on Days 4 and 8. Results No significant PK interaction was detected. On Day 4, DU alone produced small but statistically significant impairments of vigilance on DSST, MCRT and subjective alertness (BL) but no effect on other parameters. Compared to LO alone, LO+DU (Day 5) led to a decreased vigilance on DSST, MCRT and BL without altering the amnestic effects of LO. The difference between the two combinations overall tended to remit from Day 5 (first LO dose) to Day 8. Conclusions These data suggest that caution should be exercised when LO and DU are co-administered due to the potential for an increase in LO-induced sedation. Clinical Pharmacology & Therapeutics (2005) 77, P65–P65; doi: 10.1016/j.clpt.2004.12.141

Clinically unimportant pharmacokinetic drug interaction between fluvoxamine and single doses of caffeine

Background Coadministration of caffeine (CAF) and fluvoxamine (FLU) results in impaired CAF clearance and prolonged elimination half-life. The clinical importance of this interaction, attributable to CYP1A2 inhibition by FLU, remains to be firmly established. Methods In a double-blinded, 4-way, cross-over study, 7 subjects received single 250 mg doses of CAF (or placebo) concurrent with FLU (4 doses of 100 mg) or placebo. For 24 hours after CAF or placebo administration, plasma concentrations of CAF, CAF metabolites, and FLU were determined. Psychomotor performance, degree of sedation, and EEG activity were assessed as well. Results Compared to the control condition, FLU significantly reduced apparent oral clearance of CAF (105± 21 vs 9.1± 2.7 ml/min, p <0.01), prolonged elimination half-life (4.9± 0.7 vs 55.9± 10.7, p <0.01), and increased peak plasma concentrations (5.8± 0.5 vs 8.1± 0.8, p <0.05). CAF administration produced CNS-stimulating effects compared to placebo; however coadministration of FLU with CAF did not augment psychomotor performance, sedation, or EEG effects attributable to CAF. Conclusions Coadministration of FLU with single doses of CAF produced a highly significant pharmacokinetic interaction in the absence of any changes in CAF pharmacodynamics. However, the observed interaction predicts extensive CAF accumulation with daily ingestion of caffeine in FLU-treated individuals. Clinical Pharmacology & Therapeutics (2005) 77, P41–P41; doi: 10.1016/j.clpt.2004.12.050

Clinical Pharmacokinetics of Almotriptan, a Serotonin 5-HT1B/1D Receptor Agonist for the Treatment of Migraine

The pharmacokinetics of almotriptan are linear over a range of oral doses up to 200mg in healthy volunteers. The compound has a half-life of approximately 3 hours. Almotriptan is well absorbed after oral administration and the mean absolute bioavailability is 69.1%. Maximal plasma concentrations are achieved between 1.5 and 4 hours after dose administration; however, within 1 hour after administration, plasma concentrations are approximately 68% of the value at 3 hours after administration. Food does not significantly affect almotriptan absorption. Almotriptan is not highly protein bound and is extensively distributed in the body. Approximately 50% of an almotriptan dose is excreted unchanged in the urine; this is the predominant single mechanism of elimination. Renal clearance is mediated, in part, through active tubular secretion, while the balance of the almotriptan dose is metabolised to inactive compounds. The predominant route of metabolism is via monoamine oxidase-A, and cytochrome P450 (CYP) mediated oxidation (via CYP3A4 and CYP2D6) occurs to a minor extent. Almotriptan clearance is moderately reduced in elderly subjects, but the magnitude of this effect does not warrant a dose reduction. Sex has no significant effect on almotriptan pharmacokinetics. Almotriptan pharmacokinetic parameters do not differ between adolescents and adults, and absorption is not affected during a migraine attack. As expected, renal dysfunction results in reduced clearance of almotriptan. Patients with moderate-to-severe renal dysfunction should use the lowest dose of almotriptan and the total daily dose should not exceed 12.5 mg. Similar dosage recommendations are valid for patients with hepatic impairment, based on the clearance mechanisms for almotriptan. Drug-drug interaction studies were conducted between almotriptan and the following compounds: fluoxetine, moclobemide, propranolol, verapamil and ketoconazole. No significant pharmacokinetic or pharmacodynamic interactions with almotriptan were observed for fluoxetine or propranolol. Almotriptan clearance was reduced, to a modest degree, by moclobemide and verapamil, which was consistent with the contribution of monoamine oxidase-A and CYP3A4 to the metabolic clearance of almotriptan. Although ketoconazole has a greater effect on almotriptan clearance than verapamil, no dosage adjustment is required when almotriptan is given with these drugs.

Mechanism-Based Inhibition of Cytochrome P450 3A4 by Therapeutic Drugs

Consistent with its highest abundance in humans, cytochrome P450 (CYP) 3A is responsible for the metabolism of about 60% of currently known drugs. However, this unusual low substrate specificity also makes CYP3A4 susceptible to reversible or irreversible inhibition by a variety of drugs. Mechanism-based inhibition of CYP3A4 is characterised by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYP isoenzymes to reactive metabolites capable of irreversibly binding covalently to CYP3A4. Approaches using in vitro, in silico and in vivo models can be used to study CYP3A4 inactivation by drugs. Human liver microsomes are always used to estimate inactivation kinetic parameters including the concentration required for half-maximal inactivation (K(I)) and the maximal rate of inactivation at saturation (k(inact)). Clinically important mechanism-based CYP3A4 inhibitors include antibacterials (e.g. clarithromycin, erythromycin and isoniazid), anticancer agents (e.g. tamoxifen and irinotecan), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine, verapamil and diltiazem), sex steroids and their receptor modulators (e.g. gestodene and raloxifene), and several herbal constituents (e.g. bergamottin and glabridin). Drugs inactivating CYP3A4 often possess several common moieties such as a tertiary amine function, furan ring, and acetylene function. It appears that the chemical properties of a drug critical to CYP3A4 inactivation include formation of reactive metabolites by CYP isoenzymes, preponderance of CYP inducers and P-glycoprotein (P-gp) substrate, and occurrence of clinically significant pharmacokinetic interactions with coadministered drugs. Compared with reversible inhibition of CYP3A4, mechanism-based inhibition of CYP3A4 more frequently cause pharmacokinetic-pharmacodynamic drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesised CYP3A4 protein. The resultant drug interactions may lead to adverse drug effects, including some fatal events. For example, when aforementioned CYP3A4 inhibitors are coadministered with terfenadine, cisapride or astemizole (all CYP3A4 substrates), torsades de pointes (a life-threatening ventricular arrhythmia associated with QT prolongation) may occur.However, predicting drug-drug interactions involving CYP3A4 inactivation is difficult, since the clinical outcomes depend on a number of factors that are associated with drugs and patients. The apparent pharmacokinetic effect of a mechanism-based inhibitor of CYP3A4 would be a function of its K(I), k(inact) and partition ratio and the zero-order synthesis rate of new or replacement enzyme. The inactivators for CYP3A4 can be inducers and P-gp substrates/inhibitors, confounding in vitro-in vivo extrapolation. The clinical significance of CYP3A inhibition for drug safety and efficacy warrants closer understanding of the mechanisms for each inhibitor. Furthermore, such inactivation may be exploited for therapeutic gain in certain circumstances.

A Randomized Crossover Study Investigating the Influence of Ranitidine or Omeprazole on the Pharmacokinetics of Cephalexin Monohydrate

Limited data characterize pharmacokinetic interactions between cephalexin and ranitidine, and no data exist for an interaction with proton pump inhibitors. The purpose of this study was to investigate the effects of ranitidine or omeprazole administration on the pharmacokinetics and pharmacodynamics of cephalexin. A randomized single- and multiple-dose crossover study was conducted in healthy subjects ingesting cephalexin before and after steady-state administration of ranitidine or omeprazole. Time-concentration profiles were determined and pharmacokinetic parameters were characterized using noncompartmental methods. Pharmacokinetic data were analyzed in accordance with the two 1-sided test for bioequivalence. The percentage of time that serum concentrations remain above the MIC(90) during the dosing interval (T > MIC(90)) for Streptococcus pyogenes and Staphylococcus aureus associated with the pharmacokinetic profiles was calculated. The coadministration of cephalexin with ranitidine or omeprazole resulted in relatively minor changes in C(max), AUC(infinity), t(1/2), or CL/F. t(max) was significantly prolonged when cephalexin was administered with ranitidine or omeprazole. Suboptimal T > MIC(90) was observed for cephalexin irrespective of acid suppression. Delay in absorption of cephalexin resulted in a decrease in the percentage of T > MIC(90) for certain acid-suppressive regimens and pathogen combinations. With the exception of an increase in t(max), there were no significant pharmacokinetic interactions between cephalexin and ranitidine or omeprazole. Delayed t(max) associated with acid suppression may result in a diminished T > MIC(90).

Effect of zonisamide on the pharmacokinetics and pharmacodynamics of a combination ethinyl estradiol-norethindrone oral contraceptive in healthy women

Background: Several antiepileptic drugs have clinically significant pharmacokinetic interactions with oral contraceptives (OCs) that may result in contraceptive failure. Objective: The aim of this study was to assess the effect of zonisamide on the pharmacokinetics of the individual components of a combination OC (ethinyl estradiol [EE] 0.035 mg and norethindrone [NOR] 1 mg) and on pharmacodynamic variables that may be increased in the event of reduced contraceptive efficacy (concentrations of serum luteinizing hormone [LH], follicle-stimulating hormone [FSH], and progesterone). Methods: This was a single-center, open-label, 1-sequence, crossover study. Healthy, premenopausal women received the combination OC for three 28-day cycles (combination OC for 21 days, followed by placebo for 7 days). Following stabilization on the OC during the first cycle, blood was collected during cycle 2 for the determination of serum EE and NOR profiles (day 14) and serum LH, FSH, and progesterone concentrations (days 13–15). Starting on day 15 of cycle 2, zonisamide was administered orally at 100 mg/d and titrated to a target dose of 400 mg/d. EE and NOR profiles and serum LH, FSH, and progesterone concentrations were obtained again in cycle 3 (in the presence of zonisamide) and compared with those from cycle 2 (in the absence of zonisamide). Results: Thirty-seven healthy premenopausal women (mean age, 26.1 years [range, 18–51 years]; mean body weight, 65.5 kg [range, 50.4–93.1 kg]; mean height, 165.8 cm [range, 152.4–182.9 cm]) received ≥1 dose of zonisamide. Of the 33 subjects (89.2%) who completed the study, 26 (78.8%) underwent titration to a stable zonisamide dose of 400 mg/d. For EE, the mean (SD) AUC over a 24-hour dosing interval (AUC τ) was 1139 (317) pg·h/mL in cycle 2 and 1143 (312) pg·h/mL in cycle 3; the mean C max in the respective cycles was 133 (39) and 141 (46) pg/mL. For NOR, the corresponding values were 140 (48) and 159 (46) ng·h/mL for AUC τ and 21 (5.4) and 23 (6.7) ng/mL for C max. The 90% Cls for the geometric mean ratios (cycle 3:cycle 2) for AUC τ and C max fell within the accepted range for lack of interaction (0.80–1.25). There were no increases in LH, FSH, or progesterone concentrations between cycle 2 and cycle 3. Conclusions: In these healthy volunteers, steady-state zonisamide dosing had no clinically significant effect on the pharmacokinetics of EE or NOR. There was no pharmacodynamic evidence that zonisamide is likely to reduce the contraceptive effectiveness of OCs containing EE and NOR.

Simvastatin Does Not Have a Clinically Significant Pharmacokinetic Interaction With Fenofibrate in Humans

Simvastatin and fenofibrate are both commonly used lipid-regulating agents with distinct mechanisms of action, and their coadministration may be an attractive treatment for some patients with dyslipidemia. A 2-period, randomized, open-label, crossover study was conducted in 12 subjects to determine if fenofibrate and simvastatin are subject to a clinically relevant pharmacokinetic interaction at steady state. In treatment A, subjects received an 80-mg simvastatin tablet in the morning for 7 days. In treatment B, subjects received a 160-mg micronized fenofibrate capsule in the morning for 7 days, followed by a 160-mg micronized fenofibrate capsule dosed together with an 80-mg simvastatin tablet on days 8 to 14. Because food increases the bioavailability of fenofibrate, each dose was administered with food to maximize the exposure of fenofibric acid. The steady-state pharmacokinetics (AUC(0-24h), C(max), and t(max)) of active and total HMG-CoA reductase inhibitors, simvastatin acid, and simvastatin were determined following simvastatin administration with and without fenofibrate. Also, fenofibric acid steady-state pharmacokinetics were evaluated with and without simvastatin. The geometric mean ratios (GMRs) for AUC(0-24h) (80 mg simvastatin [SV] + 160 mg fenofibrate)/(80 mg simvastatin alone) and 90% confidence intervals (CIs) were 0.88 (0.80, 0.95) and 0.92 (0.82, 1.03) for active and total HMG-CoA reductase inhibitors. The GMRs and 90% CIs for fenofibric acid (80 mg SV + 160 mg fenofibrate/160 mg fenofibrate alone) AUC(0-24h) and C(max) were 0.95 (0.88, 1.04) and 0.89 (0.77, 1.02), respectively. Because both the active inhibitor and fenofibric acid AUC GMR 90% confidence intervals fell within the prespecified bounds of (0.70, 1.43), no clinically significant pharmacokinetic drug interaction between fenofibrate and simvastatin was concluded in humans. The coadministration of simvastatin and fenofibrate in this study was well tolerated.

Pharmacokinetic interaction between ezetimibe and lovastatin in healthy volunteers*

SUMMARYBackground: Ezetimibe (Zetia†) is a novel inhibitor of intestinal absorption of cholesterol that is approved for the treatment of primary hypercholesterolemia. In a separate pilot study, co-administration of ezetimibe and lovastatin resulted in a significant pharmacodynamic interaction, leading to an additive reduction in LDL-C. The current study was designed to further investigate the potential for pharmacokinetic interaction between ezetimibe and lovastatin.Methods: This was a randomized, open-label, 3-way crossover study in 18 healthy adult volunteers. All subjects received the following treatments orally once daily for 7 days: ezetimibe 10 mg, lovastatin 20 mg, or ezetimibe 10 mg plus lovastatin 20 mg. Plasma samples obtained on day 7 were evaluated for steady-state pharmacokinetics of ezetimibe (unconjugated), total ezetimibe (ezetimibe and ezetimibe-glucuronide conjugate), lovastatin, and β-hydroxylovastatin.Results: Co-administration of ezetimibe with lovastatin did not affect the pharmacokinetics of ezetimibe. There were no significant differences in the exposure to total ezetimibe, ezetimibe-glucuronide and ezetimibe after co-administration with lovastatin vs. ezetimibe given alone. Co-administration of ezetimibe with lovastatin had no significant effect on the exposure to either lovastatin or β-hydroxylovastatin. The point estimates based on the log-transformed Cmax and AUC values for lovastatin and β-hydroxylovastatin were 113% and 119%, respectively, for co-administration of ezetimibe with lovastatin vs. lovastatin administration alone. Co-administration therapy with ezetimibe and lovastatin was safe and well tolerated.Conclusions: Ezetimibe did not significantly affect the pharmacokinetics of lovastatin or β-hydroxylovastatin and vice versa. Co-administration of ezetimibe and lovastatin is unlikely to cause a clinically significant pharmacokinetic drug interaction.

Pharmacodynamic interaction between ezetimibe and rosuvastatin

SUMMARYBackground: Ezetimibe is a lipid-lowering drug indicated for the treatment of hypercholesterolemia as co-administration with HMG-CoA reductase inhibitors (statins) or as monotherapy. The primary objectives of this study were to evaluate the pharmacodynamic effects and safety of the co-administration of ezetimibe and the new statin rosuvastatin. A secondary objective was to examine the potential for a pharmacokinetic interaction between ezetimibe and rosuvastatin.Methods: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study in healthy hypercholesterolemic subjects (untreated low-density lipoprotein cholesterol [LDL-C] ≥ 130 mg/dL [3.37 mmol/L]). After the outpatient screening and NCEP Step I diet stabilization periods, 40 subjects were randomized to one of the 4 following treatments: rosuvastatin 10 mg plus ezetimibe 10 mg (n = 12); rosuvastatin 10 mg plus placebo (matching ezetimibe 10 mg) (n = 12); ezetimibe 10 mg plus placebo (matching ezetimibe 10 mg) (n = 8); or placebo (2 tablets, matching ezetimibe 10 mg) (n = 8). All study treatments were administered once daily in the morning for 14 days as part of a 16-day inpatient confinement period. Fasting serum lipids were assessed pre-dose on days 1 (baseline), 7, and 14 by direct quantitative assay methods. Safety was evaluated by monitoring laboratory tests and recording adverse events. Blood samples were collected for ezetimibe and rosuvastatin pharmacokinetic evaluation prior to the first and last dose and at frequent intervals after the last dose (day 14) of study treatment. Plasma ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and rosuvastatin concentrations were determined by validated liquid chromatography with tandem mass spectrometric detection (LC–MS/MS) assay methods.Results: All active treatments caused statistically significant ( p ≤ 0.02) decreases in LDL-C concentration versus placebo from baseline to day 14. The co-administration of ezetimibe and rosuvastatin caused a significantly ( p < 0.01) greater reduction in LDL-C and total cholesterol than either drug alone. In this 2-week inpatient study with restricted physical activity there was no apparent effect of any treatment on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The co-administration of ezetimibe and rosuvastatin caused a significantly ( p < 0.01) greater percentage reduction in mean LDL-C (–61.4%) than rosuvastatin alone (–44.9%), with a mean incremental reduction of –16.4% (95%CI –26.3 to –6.53). Reported side effects were generally mild, nonspecific, and similar among treatment groups. There were no significant increases or changes in clinical laboratory tests, particularly those assessing muscle and liver function. There was no significant pharmacokinetic drug interaction between ezetimibe and rosuvastatin.Conclusions: Co-administration of ezetimibe 10 mg with rosuvastatin 10 mg daily caused a significant incremental reduction in LDL-C compared with rosuvastatin alone. Moreover, co-administering ezetimibe and rosuvastatin was well tolerated in patients with hypercholesterolemia.

There are no significant pharmacokinetic interactions between boosted-dosage saquinavir/ritonavir and tenofovir disoproxil fumarate,

There are no significant pharmacokinetic interactions between boosted-dosage saquinavir/ritonavir and tenofovir disoproxil fumarate,

Pharmacokinetic (PK) interaction study of sirolimus (SRL) and cyclosporine (CSA)

SRL (Rapamune®) is an effective immunosuppressant currently marketed worldwide for the prophylaxis of renal allograft rejection. The interaction between SRL 5 mg (oral solution) and CsA 300 mg (Neoral® capsules) when administered simultaneously and 2 hours apart was assessed in a randomized, open-label, 5-period crossover study in 33 healthy male subjects (age 19-43 years, weight 58–89 kg). The subjects received a single oral dose of SRL alone (A), CsA alone (B), SRL and CsA together (C), SRL 2 hours after CsA (D), or SRL 2 hours before CsA (E). Whole blood SRL was assayed by HPLC with mass spectrometric detection (HPLC/MS/MS), and whole blood CsA by immunoassay. Geometric least-squares (GLS) mean ratios and 90% confidence intervals (CIs) were computed for treatment comparisons. Reference treatments for equivalence tests were either A (SRL alone) or B (CsA alone). A GLS mean ratio between 80% to 125% showed equivalence. CsA significantly increased SRL Cmax and AUC during simultaneous administration (by 117% and 183%, respectively) and when SRL was administrated 2 hours after CsA (by 126% and 141%, respectively). CsA did not affect SRL PK when SRL was administrated 2 hours before CsA. SRL did not affect the PK of CsA, regardless of the timing of administration.Table In conclusion, CsA significantly increased SRL whole blood exposure when SRL and CsA were administered simultaneously and when SRL was given 2 hours after CsA. However, no significant PK interaction was observed when SRL was administered 2 hours before CsA. Clinical Pharmacology & Therapeutics (2004) 75, P33–P33; doi: 10.1016/j.clpt.2003.11.126 Table 1. GLS mean ratios (90% CI)* for whole blood SRL and CsA PK parameters SRL CsA C vs A D vs A E vs A C vs B D vs B E vs B * Equivalence Window = 80% to 125%. Cmax 217 (196–241) 226 (204–251) 98 (88- 109) 105 (96–115) 97 (89–116) 93 (86–102) AUC 283 (257–311) 241 (219- 265) 99 (90–109) 105 (100–110) 101 (96–106) 94 (89–99) t1/2 87 (82–91) 87 (83–92) 97 (92–103) 95 (90–100) 104 (99–109) 99 (94–104)

No clinically significant interactions between the oral direct thrombin inhibitor ximelagatran and amiodarone, atorvastatin, or digoxin

Background The oral direct thrombin inhibitor ximelagatran has shown clinical benefit in patients with atrial fibrillation at risk of stroke. The potential for interaction of ximelagatran with amiodarone, atorvastatin, or digoxin, was assessed in 3 randomized studies in healthy volunteers. Methods: Study 1 was a placebo-controlled, parallel-group study (n=26) with ximelagatran (36mg) or placebo BID for 8 days and amiodarone (single 600mg oral dose) on Day 4. Study 2 was a crossover study (n=16) with atorvastatin (single 40mg oral dose) during one treatment period and ximelagatran (36mg BID for 5 days) plus a single dose of atorvastatin (40mg) on Day 4 during the other treatment period. Study 3 was a double-blind, crossover study (n=16) with ximelagatran (36mg) or placebo BID for 8 days and digoxin (single 0.5mg dose) on Day 4. Results: For melagatran, the active form of ximelagatran, AUC and Cmax geometric mean ratios (90% CI) for combined therapy relative to monotherapy with either drug were within or only slightly outside predefined bounds for no interaction. Similarly, no relevant changes were observed for the AUC and Cmax of amiodarone, atorvastatin, or digoxin. None of the coadministered drugs affected the concentration–effect relationship of melagatran on activated partial thromboplastin time. Conclusions: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when ximelagatran was administered with amiodarone, atorvastatin, or digoxin. Clinical Pharmacology & Therapeutics (2004) 75, P78–P78; doi: 10.1016/j.clpt.2003.11.294

There are no significant pharmacokinetic interactions between sorafenib* and irinotecan

There are no significant pharmacokinetic interactions between sorafenib* and irinotecan

Repaglinide : a pharmacoeconomic review of its use in type 2 diabetes mellitus.

Repaglinide : a pharmacoeconomic review of its use in type 2 diabetes mellitus.

No clinically significant pharmacokinetic interactions between voriconazole and indinavir in healthy volunteers

Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19 and to a lesser extent by CYP3A4. Protease inhibitors, such as indinavir, are also metabolized by cytochrome P450 (mainly CYP3A4). As these drugs are likely to be coadministered, these studies were performed to assess the pharmacokinetic interactions, safety and toleration of these drugs when taken together. Two randomized placebo-controlled studies were conducted in healthy male volunteers. Study A was an open parallel-group study of the effect of indinavir on the steady-state pharmacokinetics of voriconazole in 18 volunteers (nine subjects in each group). Subjects received voriconazole 200 mg twice daily (days 1-7), then voriconazole 200 mg twice daily + indinavir 800 mg or placebo three times daily (days 8-17). Study B was a double-blind, randomized, two-way crossover study of the effect of voriconazole on the steady-state pharmacokinetics of indinavir in 14 volunteers. They received indinavir 800 mg three times daily + voriconazole 200 mg or placebo twice daily for two 7-day treatment periods separated by a washout period of at least 7 days. Pharmacokinetic parameters were compared within treatment groups at days 7 and 17 in Study A and between treatment groups on day 7 of each period in Study B. All adverse events were recorded. Study A: Seventeen subjects were evaluable for pharmacokinetic analysis (eight voriconazole + indinavir, nine voriconazole + placebo). The day 17/day 7 ratios for Cmax and AUCtau were estimated as 102%[90% confidence interval (CI) 91, 114] and 107% (90% CI 98, 118), respectively. Study B: Fourteen subjects were evaluable for pharmacokinetic analysis in each treatment period. The ratios between the geometric means for indinavir + voriconazole vs. indinavir + placebo were: Cmax, 91% (90% CI 83, 101), AUCtau, 87% (90% CI 77, 100), and Cmin, 101% (90% CI 82, 125). Trough plasma concentrations of indinavir were above the concentration required to inhibit HIV replication (IC95) in both treatment periods. Voriconazole coadministered with indinavir was well tolerated in both studies. The coadministration of voriconazole and indinavir in healthy volunteers had no clinically significant effect on the pharmacokinetics of either voriconazole or indinavir.

P.4.032 Cognitive influence of topiramate in children

Rosuvastatin is indicated for hypercholesterolemia or dyslipidemia and metformin mainly for type 2 diabetes. These 2 drugs are frequently prescribed in combination due to the high comorbidity of the 2 diseases. However the nature of pharmacokinetic interaction between the 2 drugs has not been previously investigated. The purpose of our study was to investigate the pharmacokinetic interaction between rosuvastatin and metformin in healthy Korean male volunteers.This was a randomized, open-label, 6-sequence, 3-period, crossover, multiple-dose study. Eligible subjects, aged 20 to 50 years and within 20% of the ideal body weight, received 1 of the following 3 treatments for each period once daily for 5 consecutive days with a 10-day washout period between the treatments: monoadministration of rosuvastatin 10 mg tablet, monoadministration of metformin 750 mg tablet, and coadministration of rosuvastatin 10 mg tablet with metformin 750 mg tablet. Blood samples were collected up to 72 hours after the last dose and pharmacokinetic parameters for rosuvastatin and metformin were compared between combination and monotherapy. Adverse events were investigated and evaluated based on subject interviews and physical examinations.Among the 36 enrolled subjects, 31 completed the study. The coadministration of rosuvastatin with metformin produced a significant pharmacokinetic interaction in rosuvastatin Css,max, with the 90% CI for the geometric mean ratio (coadministration:monoadministration) being 110.27% to 136.39% (P = 0.0029), whereas no significant interaction was observed in rosuvastatin AUCtau, yielding the 90% CI of 104.41% to 118.95%. When metformin was coadministered with rosuvastatin, no significant pharmacokinetic interaction was observed for Css,max and AUCtau of metformin, yielding the 90% CIs of the geometric mean ratio for coadministration to monoadministration as 87.38% to 102.54% and 86.70% to 99.08%, respectively. Overall, 19 mild and 1 moderate adverse events occurred in 12 subjects, with no significant differences in the incidence among the 3 treatments.Although the Css,max of rosuvastatin was significantly influenced by coadministration with metformin, the degree of interaction seen was considered clinically insignificant, with no significant interaction observed in the other pharmacokinetic measures between the 2 drugs. These results imply that drug effects of rosuvastatin and metformin will also not be significantly influenced by coadministration of the 2 drugs. All treatments were well tolerated and no serious adverse events occurred. ClinicalTrials.gov identifier: NCT01526317.

LEVETIRACETAM: A NEW THERAPEUTIC OPTION FOR REFRACTORY EPILEPSY

SUMMARYLevetiracetam (LEV) is the most recently licensed antiepileptic drug (AED) for adjunctive therapy of partial seizures. Its mechanism of action is uncertain but it exhibits a unique profile of anticonvulsant activity in models of chronic epilepsy. Three randomised, double‐blind, placebo‐controlled trials enrolling 904 patients with refractory partial epilepsy have demonstrated the efficacy of LEV as adjunctive therapy, with a responder rate (≥50% reduction in seizure frequency) of 28–41%. Long‐term efficacy studies suggest retention rates of 60% after one year, with 13% of patients seizure‐free for six months of the study and 8% seizure‐free for one year. Adverse effects of LEV, including somnolence, lethargy and dizziness, were generally mild and the frequency of incidents was not significantly different between the active treatment and placebo groups in clinical trials. LEV has no clinically significant pharmacokinetic interactions (PKI) with other AEDs, or with commonly prescribed medications. Preliminary data suggest that LEV has efficacy in primary generalised epilepsy and further randomised trials are under way. The combination of potent antiepileptic properties with a relatively mild adverse effect profile makes LEV an attractive adjunctive therapy for partial seizures.

Pharmacodynamic analysis of the interaction between tiagabine and midazolam with an allosteric model that incorporates signal transduction.

The objective of this study was to characterize quantitatively the pharmacodynamic interaction between midazolam (MDL), an allosteric modulator of the gamma-aminobutyric acid subtype A (GABAA) receptor, and tiagabine (TGB), an inhibitor of synaptic GABA uptake. The in vivo concentration-response relation of TGB was determined through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Rats received a single intravenous dose of 10 mg/kg TGB in the absence and the presence of a steady-state plasma concentration of MDL. The EEG response in the 11.5- to 30-Hz frequency band was used as the pharmacodynamic end point. Infusion of MDL resulted in a mean steady-state plasma concentration of 66 +/- 3 ng/ml. A significant pharmacokinetic interaction with TGB was observed. MDL inhibited TGB clearance by 20 +/- 7 ml/min/kg from the original value of 89 +/- 6 ml/min/kg. However, no changes in plasma protein binding of both drugs were observed. The concentration-EEG relation of TGB was described by the sigmoid-Emax model. The pharmacodynamic parameter estimates of TGB were: Emax = 327 +/- 10 microV, EC50 = 392 +/- 20 ng/ml, and nH = 3.1 +/- 0.3. These values were not significantly different in the presence of MDL. Factors that may explain the lack of synergism were identified by a mechanism-based interaction model that separates the receptor activation from the signal-transduction process. High efficiency of signal transduction and the presence of a baseline response were shown to diminish the degree of synergism. We conclude that the in vivo pharmacodynamic interaction between MDL and TGB is additive rather than synergistic. This strongly suggests that allosteric modulation of the antiseizure activity of a GAT-1 inhibitor by a benzodiazepine does not offer a therapeutic advantage.