Lack Of Pharmacokinetic Interaction Research Articles

Lack of pharmacokinetic interaction between derazantinib and naringin in rats

Context Derazantinib—an orally bioavailable, ATP competitive, multikinase inhibitor—has strong activity against fibroblast growth factor receptors (FGFR)2, FGFR1, and FGFR3 kinases. It has preliminary antitumor activity in patients with unresectable or metastatic FGFR2 fusion-positive intrahepatic cholangiocarcinoma (iCCA). Objective This experiment validates a novel sensitive and rapid method for the determination of derazantinib concentration in rat plasma by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), and applies it to the study of drug-drug interaction between derazantinib and naringin in vivo. Materials and methods A Xevo TQ-S triple quadrupole tandem mass spectrometer was used for mass spectrometry monitoring in selective reaction monitoring (SRM) mode with transitions of m/z 468 96 → 382.00 for derazantinib and m/z 488.01 → 400.98 for pemigatinib, respectively. The pharmacokinetics of derazantinib (30 mg/kg) was investigated in Sprague-Dawley (SD) rats divided into two groups (with the oral pretreatment of 50 mg/kg naringin or not). Results The newly optimized UPLC-MS/MS method was suitable for the determination of derazantinib in rat plasma. It was also successfully employed to evaluate the effect of naringin on derazantinib metabolism in rats. After pretreatment with naringin, there was no significant difference in the pharmacokinetic parameters (AUC0→t, AUC0→∞, t1/2, CLz/F, and Cmax) of derazantinib when compared with derazantinib alone. Conclusion Co-administration of naringin with derazantinib was not associated with significant changes in pharmacokinetic parameters. Thus, this study suggests that the combination of derazantinib with naringin can safely be administered concomitantly without dose adjustment.

Lack of pharmacokinetic interaction between the HIV-1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women.

AimsGSK3640254 is a next‐generation maturation inhibitor likely to be coadministered with combined oral contraceptives in HIV‐positive women.MethodsThis phase I, open‐label, 1‐way study assessed pharmacokinetic and pharmacodynamic interactions of GSK3640254 200 mg and ethinyl oestradiol 0.03 mg/levonorgestrel 0.15 mg once daily in healthy female participants who received ethinyl oestradiol/levonorgestrel for 10 days with a moderate‐fat meal after which GSK3640254 was added from Days 11 to 21. Primary endpoints were area under the plasma concentration–time curve to the end of the dosing interval (AUC0‐t), maximum observed concentration (Cmax) and plasma concentration at the end of the dosing interval (Cτ) for ethinyl oestradiol and levonorgestrel. Serum follicle‐stimulating hormone, luteinizing hormone and progesterone concentrations were determined. Adverse events were monitored.ResultsAmong 23 enrolled participants, 17 completed the study. Geometric least squares mean ratios (with vs. without GSK3640254) of AUC0‐t, Cmax and Cτ were 0.974, 0.970 and 1.050 for ethinyl oestradiol and 1.069, 1.032 and 1.083 for levonorgestrel, respectively. Three participants had elevated progesterone levels, which occurred before GSK3640254 administration in 2 participants. No participants had elevated follicle‐stimulating hormone or luteinizing hormone values. Fourteen participants (61%) reported adverse events. Four participants reported asymptomatic elevated transaminase levels meeting liver‐stopping criteria; of these, 3 events occurred before GSK3640254 administration and led to study withdrawal.ConclusionEthinyl oestradiol/levonorgestrel plus GSK3640254 coadministration did not affect steady‐state pharmacokinetics or pharmacodynamics of ethinyl oestradiol and levonorgestrel in healthy female participants. No major tolerability findings were reported. Elevated liver transaminase levels were probably due to ethinyl oestradiol/levonorgestrel.

Pharmacokinetic evaluation of roxithromycin and ciprofloxacin in treating complicated avian mycoplasmosis in broiler chickens

The use of roxithromycin along with ciprofloxacin is having potential to be a promising antimicrobial therapy to treat complicated avian mycoplasmosis in broiler chickens. The present research was undertaken to study the influence of roxithromycin (20 mg/kg body weight) and ciprofloxacin (10 mg/kg body weight) on the oral pharmacokinetics of each other, when both drugs are concomitantly administered in eight healthy male broiler chickens (n=8) and to establish their therapeutic dosage regimens. Their plasma concentrations were assayed by validated ultra high performance liquid chromatography (UHPLC) methods using UV detector. Oral pharmacokinetic parameters were calculated from plasma concentration versus time data based on non-compartmental analysis. Statistically, plasma roxithromycin concentration was significantly higher at one time point only (0.5 h) and plasma ciprofloxacin concentration was significantly lower at the time point of 2 h only when used in combination, in comparison to their respective values obtained after their alone administrations. The pharmacokinetic parameters of roxithromycin and ciprofloxacin showed no significant effect on values of either drug when given in combination and there was a lack of pharmacokinetic interaction between the two antimicrobials. The predicted effective oral dose rate of roxithromycin was 20 mg/kg body weight, every 12 h, and that of ciprofloxacin was 10 mg/kg body weight, every 24 h, to treat complicated avian mycoplasmosis in broiler chickens.

No Relevant Pharmacokinetic Drug-Drug Interaction Between the Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin and Lobeglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, in Healthy Subjects.

PurposeCombination therapy with insulin-independent sodium-glucose cotransporter 2 inhibitors and thiazolidinedione drugs, such as lobeglitazone, has been reported to elicit potential additive efficacy in glycemic control in type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetic (PK) drug–drug interactions between empagliflozin and lobeglitazone in healthy subjects.Subjects and MethodsA randomized, open-label, multiple-dose study was conducted in 30 healthy subjects using a three-treatment, six-sequence, three-way crossover design. Subjects received one of the following treatments once daily for 5 days in each period: 25 mg empagliflozin, 0.5 mg lobeglitazone sulfate, or a combination. Serial blood sampling before every dose and up to 24 h after the last dose was performed during each treatment period. The PK parameters were estimated using noncompartmental methods with the plasma empagliflozin and lobeglitazone concentrations. The absence of a PK interaction was construed as the 90% confidence interval (90% CI) of maximum concentration at steady state (Cmax,ss) and area under the concentration-time curve over the dosing interval (AUCtau) for combination therapy-to-monotherapy ratios within the limits of 0.80–1.25.ResultsThe steady-state plasma empagliflozin and lobeglitazone concentration-time profiles of combination therapy and monotherapy were comparable in the 25 subjects who completed the study. Coadministration of empagliflozin with lobeglitazone did not affect empagliflozin PK (with 90% CIs of 0.956–1.150 and 0.945–1.133 for Cmax,ss and AUCtau, respectively). Likewise, empagliflozin did not affect lobeglitazone Cmax,ss or AUCtau (with 90% CIs of 0.869–0.995 and 0.851–1.018, respectively). All treatment groups tolerated mild adverse events well.ConclusionThe lack of PK interactions between lobeglitazone and empagliflozin in combination therapy, along with their good tolerability, indicates that the two drugs can be coadministered without dose adjustment.Trial Registration NumberNCT02854748, Registered on August 7, 2016.

Lack of pharmacokinetic interaction between single oral doses of letermovir (MK-8228) and fluconazole in healthy subjects

Lack of pharmacokinetic interaction between single oral doses of letermovir (MK-8228) and fluconazole in healthy subjects

Lack of pharmacokinetic interaction between fluvastatin and green tea in healthy volunteers.

The objective of this study is to assess the effects of green tea and its major catechin component, (-)-epigallocatechin gallate (EGCG), on CYP2C9-mediated substrate metabolism in vitro, and the pharmacokinetics of fluvastatin in healthy volunteers. The metabolism of diclofenac and fluvastatin in human recombinant CYP2C9 was investigated in the presence of EGCG. In a randomized three-phase crossover study, 11 healthy volunteers ingested a single 20-mg dose of fluvastatin with green tea extract (GTE), containing 150mg of EGCG, along with water (300mL), brewed green tea (300mL), or water (300mL) after overnight fasting. Plasma concentrations of fluvastatin and EGCG were measured by ultra-performance liquid chromatography with fluorescence detection and a single mass spectrometer. EGCG inhibited diclofenac 4'-hydroxylation and fluvastatin degradation with IC50 of 2.23 and 48.04μM, respectively. Brewed green tea used in the clinical study also dose-dependently inhibited the metabolism of diclofenac and fluvastatin in vitro. However, no significant effects of GTE and brewed green tea were observed in plasma concentrations of fluvastatin. The geometric mean ratios with 90% CI for area under the plasma concentration-time curve (AUC0-∞) of fluvastatin were 0.993 (0.963-1.024, vs. brewed green tea) and 0.977 (0.935-1.020, vs. GTE). Although in vitro studies indicated that EGCG and brewed green tea produce significant inhibitory effects on CYP2C9 activity, the concomitant administration of green tea and fluvastatin in healthy volunteers did not influence the pharmacokinetics of fluvastatin.

Lack of Pharmacokinetic Interaction between Antipsychotics (Quetiapine, Clozapine and Olanzapine) and the Beta-Blockers Metoprolol, Propranolol, Bisoprolol and Nebivolol Except between Carvedilol and the Antipsychotics Quetiapine and Clozapine

The purpose of this study was to evaluate a potential pharmacokinetic interaction between antipsychotics (quetiapine QUE, clozapine CLO and olanzapine OLA) and beta-blockers (metoprolol MET, propranolol PRO, bisoprolol BIS, nebivolol NEB and carvedilol CAR). Antipsychotics and beta-blockers are metabolized by the same cytochrome-P450 (CYP)-isoenzymes, which are inhibited by representatives of both substance classes. Pooled human liver microsomes (HLM) and recombinant CYP isoenzymes were used to determine whether the investigated antipsychotics and beta-blockers inhibit the metabolism of each other. Drug concentrations have been measured by high performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Experiments with HLM showed that the metabolism of QUE as well as CLO slowed down in presence of CAR. There was no significant difference between the metabolism of the antipsychotics alone and the metabolism in combination with BIS, NEB and the two known CYP2D6-inhibitors MET and PRO. Experiments with recombinant CYP2D6 demonstrated an inhibitory effect on the metabolism of QUE and CLO by MET, PRO, NEB and CAR. The results suggest that CAR is also an inhibitor of other CYP enzymes, which are involved in the metabolism of CLO and QUE. It is assumed that CYP2D6 is a minor pathway of the antipsychotics and that the CYP2D6-inhibitory-effect of MET, PRO and NEB is compensated through a higher metabolism rate via the metabolic pathways of the other CYP-isoforms.

The use of combinations of monoclonal antibodies in clinical oncology.

Treatment with monoclonal antibodies is becoming increasingly important in clinical oncology. These antibodies specifically inhibit signaling pathways in tumor growth and/or induce immunological responses against tumor cells. By combining monoclonal antibodies several pathways may be targeted simultaneously, potentially leading to additive or synergistic effects. Theoretically, antibodies are very suitable for use in combination therapy, because of limited overlapping toxicity and lack of pharmacokinetic interactions. In this article an overview is given of preclinical and clinical data on twenty-five different combinations of antibodies in oncology. Some of these combinations have proven clinical benefit, for example the combination of trastuzumab and pertuzumab in HER2-positive breast cancer, which exemplifies an additive or synergistic effect on antitumor activity in clinical studies and the combination of nivolumab and ipilimumab, which results in significant increases in progression-free and overall survival in patients with advanced melanoma. However, other combinations may lead to unfavorable results, such as bevacizumab with cetuximab or panitumumab in advanced colorectal cancer. These combinations result in shorter progression-free survival and increased toxicity compared to therapy with a single antibody. In summary, the different published studies showed widely varying results, depending on the combination of antibodies, indication and patient population. More preclinical and clinical studies are necessary to unravel the mechanisms behind synergistic or antagonistic effects of combining monoclonal antibodies. Most research on combination therapies is still in an early stage, but it is expected that for several tumor types the use of combination therapy of antibodies will become standard of care in the near future.

Influence of N-(p-acetylphenyl)-p-isopropoxyphenylsuccinimide on the protective action of classical antiepileptic drugs against maximal electroshock-induced seizures in mice

The aim of this study was to determine the effects of N-(p-acetylphenyl)-p-isopropoxyphenylsuccinimide (APIPPS) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) in the maximal electroshock (MES)-induced seizures in mice. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Total brain AED concentrations were measured with fluorescence polarization immunoassay to ascertain whether any observed effects were consequent to a pharmacodynamic and/or a pharmacokinetic interaction between APIPPS and classical AEDs. Results indicate that APIPPS administered intraperitoneally at a dose of 150 mg/kg significantly elevated the threshold for electroconvulsions in mice. APIPPS at lower doses of 25, 50 and 100 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, APIPPS at 100 mg/kg significantly enhanced the anticonvulsant activity of PB and VPA, but not that of CBZ or PHT, in the MES test in mice. APIPPS at a dose of 50 mg/kg significantly potentiated the anticonvulsant action of VPA, but not that of PB in the mouse MES model. Pharmacokinetic experiment revealed that APIPPS did not alter total brain concentrations of PB or VPA in mice. Summing up, the enhanced anticonvulsant action of PB and VPA by APIPPS in the mouse MES model and lack of pharmacokinetic interactions between drugs, make the combinations of APIPPS with PB and VPA of importance for further experimental and clinical studies. The combinations of APIPPS with CBZ and PHT are neutral from a preclinical viewpoint.

Influence of CYP3A4 Induction/Inhibition on the Pharmacokinetics of Vilazodone in Healthy Subjects

PurposeVilazodone is a serotonin reuptake inhibitor and 5-HT1A partial agonist approved for the treatment of major depressive disorder in adults. Vilazodone seems to be metabolized primarily by the cytochrome P-450 (CYP) 3A4 isozyme and non-CYP–mediated pathways; concomitant use of drugs that affect CYP3A4 activity could potentially alter systemic exposure to vilazodone. The present studies evaluated whether CYP3A4 inhibition (study 1) or induction (study 2) affected the pharmacokinetics of vilazodone. MethodsParticipants were healthy adult volunteers. Study 1 was conducted in 2 parts and evaluated the pharmacokinetics of single-dose vilazodone administered with multiple-dose (200 mg once daily) ketoconazole, a CYP3A4 inhibitor. Part 1 was an open-label pharmacokinetic assessment of a single 5-mg vilazodone dose with or without ketoconazole. Part 2 was a randomized, double-blind, placebo-controlled, crossover study comparing vilazodone pharmacokinetics after a single 10-mg dose alone or co-administered with ketoconazole or placebo. Study 2 was an open-label, multiple-dose, single-sequence study evaluating the effect of steady-state carbamazepine, a CYP3A4 substrate and inducer, on the pharmacokinetics of steady-state vilazodone (40 mg once daily). Primary pharmacokinetic parameters for both studies were AUC and Cmax for vilazodone. Lack of pharmacokinetic interaction was concluded if the 90% CIs of the ratio of vilazodone plus the CYP3A4 inhibitor/inducer relative to vilazodone alone (or plus placebo) for AUC and Cmax were within the 80% to 125% range. Subject-reported and investigator-identified adverse events (AEs), laboratory values, vital signs, and 12-lead ECG parameters were recorded. FindingsIn study 1/parts 1 and 2 (n = 15 and 22 enrolled, respectively), mean vilazodone AUC increased 42% and 51%, respectively, in the presence of ketoconazole (expected to be at steady state) versus vilazodone alone (part 1) or with placebo (part 2). The upper limit of the 90% CIs for the vilazodone AUC and Cmax geometric mean ratios exceeded 125%. In study 2 (n = 30 enrolled), co-administration of vilazodone and the carbamazepine extended-release formulation decreased mean steady-state vilazodone exposure ~45%, and the 90% CIs for the vilazodone AUC and Cmax geometric mean ratios were not within the range of 80% to 125%. In both studies, most AEs were of mild intensity, and gastrointestinal AEs predominated. ImplicationsThese results suggest that up to a 50% decrease of vilazodone dosage should be considered when it is given in combination with strong CYP3A4 inhibitors; conversely, increasing the vilazodone dosage up to a maximum of 80 mg/d should be considered when it is given in combination with strong CYP3A4 inducers. (Study registration numbers: SB-659746/029; VLZ-PK-02.)

Lack of Pharmacokinetic Interaction between Rilpivirine and Integrase Inhibitors Dolutegravir and GSK1265744

Dolutegravir (DTG) and GSK1265744 are HIV integrase inhibitors (INIs) in clinical development. The oral formulation of rilpivirine (RPV), a nonnucleoside reverse transcriptase inhibitor (NNRTI), has been approved for treatment-naive HIV infection. Long-acting depot injections of GSK1265744 and RPV are also being developed. This study evaluated the potential for drug interactions between RPV and these INIs. This phase 1, open-label, two-cohort, three-period, single-sequence crossover study evaluated oral coadministration of RPV with DTG or GSK1265744. Healthy subjects received DTG (50 mg every 24 h for 5 days) or GSK1265744 (30 mg every 24 h for 12 days) in period 1 followed by a washout, RPV (25 mg every 24 h for 11 or 12 days) in period 2, immediately followed by RPV (25 mg every 24 h) plus DTG (50 mg every 24 h) for 5 days or GSK1265744 (30 mg every 24 h) for 12 days in period 3. Steady-state pharmacokinetic (PK) parameters were estimated using noncompartmental analysis of data collected on the last day of each period. The combinations of RPV and DTG (n = 16) and of RPV and GSK1265744 (n = 11) were well tolerated; no grade 3 or 4 adverse events (AEs) or AE-related discontinuations were observed. The 90% confidence intervals for the area under the curve from time zero until the end of the dosage interval [AUC0-τ] and maximum concentration of drug in serum (Cmax) geometric mean ratios were within 0.8 to 1.25. Following administration of DTG + RPV, DTG and RPV Cτ increased by 22% and 21%, respectively. Following administration of GSK1265744 + RPV, RPV Cτ decreased 8%. DTG and GSK1265744 can be administered with RPV without dosage adjustment for either agent. These results support coadministration of RPV with DTG or GSK1265744 as either oral or long-acting depot injection regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01467531.).

AB0363 Coadministration of asp015k, a novel janus kinase inhibitor, with methotrexate demonstrates tolerability and lack of pharmacokinetic interactions in patients with rheumatoid arthritis

BackgroundASP015K is an oral Janus kinase (JAK) inhibitor with selectivity for JAK1/3 in development for treatment of rheumatoid arthritis (RA) and other autoimmune diseases. Methotrexate (MTX) is the most common...

Lack of Pharmacokinetic Interaction between Pilsicainide and Rifampicin in Healthy Volunteers

Lack of Pharmacokinetic Interaction between Pilsicainide and Rifampicin in Healthy Volunteers

Influence of N-hydroxymethyl-p-isopropoxyphenylsuccinimide on the anticonvulsant action of different classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Experimental epileptology is mainly focused on searching for some active compounds suppressing seizures that could become efficacious antiepileptic drugs. Accumulating evidence indicates that succinimide derivatives would be good candidates for novel antiepileptic drugs. Therefore, the aim of this study was to determine the effects of N-hydroxymethyl-p-isopropoxyphenyl-succinimide (HMIPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the maximal electroshock-induced seizure test in mice. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. Results indicate that HMIPPS administered intraperitoneally at 100mg/kg significantly elevated the threshold for electroconvulsions in mice (P<0.05). HMIPPS at doses of 12.5, 25 and 50mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, HMIPPS (50mg/kg) significantly enhanced the anticonvulsant activity of phenobarbital and valproate in the mouse maximal electroshock-induced seizure model by reducing their median effective doses (ED(50) values) from 23.25mg/kg to 16.82 mg/kg (P<0.01; for phenobarbital) and from 259.3mg/kg to 189.7 mg/kg (P<0.001; for valproate), respectively. In contrast, HMIPPS (50mg/kg) had no impact on the protective action of carbamazepine or phenytoin in the maximal electroshock seizure test in mice. HMIPPS (25mg/kg) significantly potentiated the anticonvulsant action of valproate by reducing its ED(50) value from 259.3mg/kg to 210.6 mg/kg (P>0.05), but not that of phenobarbital, phenytoin and carbamazepine in the mouse maximal electroshock-induced seizure model. Pharmacokinetic experiments revealed that HMIPPS did not alter total brain concentrations of phenobarbital or valproate in mice. Moreover, none of the examined combinations of HMIPPS (50mg/kg) with carbamazepine, phenobarbital, phenytoin and valproate (at their ED(50) values from the maximal electroshock-induced seizure test) affected motor coordination in the chimney test, long-term memory in the passive avoidance task, and muscular strength in the grip-strength test in mice, indicating no possible acute adverse effects in animals. In conclusion, the enhanced anticonvulsant action of phenobarbital and valproate by HMIPPS in the mouse maximal electroshock-induced seizure model, lack of pharmacokinetic interactions and no potential acute adverse effects make the combinations of HMIPPS with phenobarbital and valproate worthy of consideration for further experimental and clinical studies. The combinations of HMIPPS with carbamazepine and phenytoin are neutral from a preclinical viewpoint.

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

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. 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. 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. Dapagliflozin can be co-administered with pioglitazone, metformin, glimepiride or sitagliptin without dose adjustment of either drug.

Lack of Pharmacokinetic Interaction between Amdoxovir and Reduced- and Standard-Dose Zidovudine in HIV-1-Infected Individuals

Amdoxovir (AMDX) inhibits HIV-1 containing the M184V/I mutation and is rapidly absorbed and deaminated to its active metabolite, beta-D-dioxolane guanosine (DXG). DXG is synergistic with zidovudine (ZDV) in HIV-1-infected primary human lymphocytes. A recent in silico pharmacokinetic (PK)/enzyme kinetic study suggested that ZDV at 200 mg twice a day (b.i.d.) may reduce toxicity without compromising efficacy relative to the standard 300-mg b.i.d. dose. Therefore, an intense PK clinical study was conducted using AMDX/placebo, with or without ZDV, in 24 subjects randomized to receive oral AMDX at 500 mg b.i.d., AMDX at 500 mg plus ZDV at 200 or 300 mg b.i.d., or ZDV at 200 or 300 mg b.i.d. for 10 days. Full plasma PK profiles were collected on days 1 and 10, and complete urine sampling was performed on day 9. Plasma and urine concentrations of AMDX, DXG, ZDV, and ZDV-5'-O-glucuronide (GZDV) were measured using a validated liquid chromatography-tandem mass spectrometry method. Data were analyzed using noncompartmental methods, and multiple comparisons were performed on the log-transformed parameters, at steady state. Coadministration of AMDX with ZDV did not significantly change either of the plasma PK parameters or percent recovery in the urine of AMDX, DXG, or ZDV/GZDV. Larger studies with AMDX/ZDV, with a longer duration, are warranted.

Effect of arachidonyl-2′-chloroethylamide, a selective cannabinoid CB1 receptor agonist, on the protective action of the various antiepileptic drugs in the mouse maximal electroshock-induced seizure model

The aim of this study was to determine the influence of arachidonyl-2'-chloroethylamide (ACEA - a highly selective cannabinoid type 1 [CB1] receptor agonist) on the protective action and acute adverse effects of carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, and topiramate in the maximal electroshock seizure model and chimney test in mice. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles of the studied antiepileptic drugs with respect to motor coordination was assessed in the chimney test. Additionally, long-term memory and skeletal muscular strength were measured along with free plasma (non-protein bound) and total brain antiepileptic drug concentrations. To inhibit the rapid metabolic degradation of ACEA by the fatty-acid amide hydrolase, phenylmethylsulfonyl fluoride (PMSF) was used at a constant ineffective dose of 30 mg/kg. Results indicate that ACEA (2.5 mg/kg, i.p.) co-administered with PMSF (30 mg/kg, i.p.), significantly enhanced the anticonvulsant activity of phenobarbital, but not that of carbamazepine, lamotrigine, oxcarbazepine, phenytoin, or topiramate in the maximal electroshock seizure test in mice. Moreover, ACEA (2.5 mg/kg) with PMSF (30 mg/kg) had no significant impact on the acute adverse effects of all examined antiepileptic drugs in the chimney test in mice. The protective index values (as quotients of the respective TD(50) and ED(50) values denoted from the chimney and maximal electroshock seizure tests, respectively) for the combinations of ACEA (2.5 mg/kg) and PMSF (30 mg/kg) with carbamazepine, oxcarbazepine, phenobarbital, and topiramate were greater than those denoted for the antiepileptic drugs administered alone. Only, the protective index values for the combination of ACEA (2.5 mg/kg) and PMSF (30 mg/kg) with lamotrigine and phenytoin were lower than those determined for the antiepileptic drugs administered alone. Pharmacokinetic experiments revealed that ACEA (2.5 mg/kg) and PMSF (30 mg/kg) affected neither free plasma (non-protein bound) nor total brain concentrations of phenobarbital in mice. Moreover, ACEA and PMSF in combination with carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, and topiramate did not alter long-term memory or skeletal muscular strength in experimental animals. In conclusion, the enhanced anticonvulsant action of phenobarbital by ACEA and PMSF, lack of pharmacokinetic interaction and no acute adverse effects between the examined compounds, make the combination of ACEA and PMSF with phenobarbital of pivotal importance for further experimental and clinical studies. The combinations of ACEA and PMSF with carbamazepine, lamotrigine, oxcarbazepine, phenytoin, and topiramate are neutral from a preclinical viewpoint.

Study of the pharmacokinetic interaction of vildagliptin and metformin in patients with type 2 diabetes

ABSTRACTObjective: Metformin is widely used for treating patients with type 2 diabetes, often as first-line therapy; however, many patients with type 2 diabetes are unable to maintain adequate glycemic control with metformin alone. Vildagliptin, an orally active, potent and selective dipeptidyl peptidase IV (DPP-4) inhibitor, may represent an appropriate antihyperglycemic agent for combination with metformin to improve glycemic control in such patients. This study assessed the effects of coadministration of vildagliptin and metformin on the steady-state pharmacokinetics of each drug.Research design and methods: In this open-label, single-center, randomized, three-period, three-treatment crossover study, 17 patients with type 2 diabetes received vildagliptin 100 mg once daily; metformin 1000 mg once daily; or vildagliptin 100 mg once daily plus metformin 1000 mg once daily. Blood samples for pharmacokinetic sampling were taken frequently on the final day (Day 5) of each treatment period. Lack of pharmacokinetic interaction was defined as the ratio of geometric mean (GMR) and 90% confidence interval (CI) for combination:monotherapy being within the range 0.80–1.25.Results: Coadministration with metformin had no effect on vildagliptin AUC0–24 (GMR, 0.94; 90% CI 0.90, 0.99) although there was an 18% decrease in vildagliptin Cmax (GMR 0.82; 90% CI 0.73, 0.91). Coadministration with vildagliptin had no effect on metformin Cmax (GMR 1.04; 90% CI 0.94, 1.16). but caused a 15% increase in AUC0–24 (GMR 1.15; 90% CI 1.06, 1.25). Both monotherapies and combination therapy were well tolerated. Seven patients reported a total of 10 adverse events; none was serious.Conclusions: Coadministration of vildagliptin and metformin had a small effect on the pharmacokinetics of each drug in patients with type 2 diabetes; however, this is not likely to be clinically relevant. This small, open-label trial suggests that vildagliptin could be coadministered with metformin without any dose adjustment for either agent.

Influence of domperidone on pharmacokinetics, safety and tolerability of the dopamine agonist rotigotine

Rotigotine transdermal patch is a new non-ergolinic dopamine agonist developed for the treatment of Parkinson's disease and restless legs syndrome. Peripheral dopaminergic side-effects of dopamine agonists such as nausea and vomiting can be prevented by the antiemetic agent domperidone. The study results show no evidence for an interaction of domperidone on bioavailability and steady-state pharmacokinetics of transdermal rotigotine. Co-administration of domperidone and rotigotine does not require dose adjustments for rotigotine transdermal patch. To evaluate the influence of the antiemetic agent domperidone on steady-state pharmacokinetics, safety and tolerability of multiple-dose treatment of the transdermally applied non-ergolinic dopamine agonist rotigotine. Sixteen healthy male subjects (mean age 30.3 years) participated in a randomized, two-way crossover clinical trial. Treatment A consisted of transdermal rotigotine patch (2 mg (24 h)(-1), 10 cm(2), total drug content 4.5 mg) applied daily for 4 days, and concomitant oral domperidone (10 mg t.i.d.) for 5 days. For treatment B, subjects received only transdermal rotigotine treatment (daily for 4 days). Pharmacokinetic variables describing systemic exposure and renal elimination of rotigotine and metabolites, and safety and tolerability of the treatment were assessed. The primary steady-state pharmacokinetic parameters (C(max,ss) and AUC((0-24),ss)) were similar with or without co-administration of domperidone. Geometric mean ratios were close to 1 and respective 90% confidence intervals were within the acceptance range of bioequivalence (0.8, 1.25): C(max,ss) 0.96 (0.86, 1.08) and AUC((0-24),ss) 0.97 (0.87, 1.08). t(max,ss), t(1/2), secondary parameters calculated on days 4/5 after repeated patch application (C(min,ss), C(ave,ss), AUC((0-tz))) and renal elimination for unconjugated rotigotine and its metabolites were also similar with and without comedication of domperidone. A reduction in the dopaminergic side-effect nausea was seen with domperidone comedication. No changes of pharmacokinetic parameters describing systemic exposure and renal elimination of rotigotine were observed when domperidone was administered concomitantly with rotigotine. The lack of pharmacokinetic interactions indicates that a dose adjustment of rotigotine transdermal patch is not necessary with concomitant use of domperidone.

The potential of DMXAA (ASA404) in combination with docetaxel in advanced prostate cancer

5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a vascular disrupting agent that has demonstrated efficacy in combination with taxane-based chemotherapy in patients with advanced cancer. Complementary modes of action, a lack of pharmacokinetic interaction and distinct adverse effect profiles provide a strong rationale for combining these anticancer agents. In a Phase II trial in men with hormone refractory prostate cancer, DMXAA (ASA404) in combination with docetaxel achieved a prostate-specific antigen response in more patients than docetaxel therapy alone, and was generally well tolerated. Further clinical evaluation of this combination in this patient population is warranted.