Home About us Contact
|
Home About us Contact | ||
|
|
||
Pharmacokinetic Assessments (pharmacokinetic + assessment)
Selected AbstractsSafety Pharmacology, Toxicology and Pharmacokinetic Assessment of Recombinant Human ,-Interferon Produced from CHO-SS CellsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2006Victor E. Buckwold Here we provide an overview of our preclinical safety evaluation of the fully-glycosylated human IFN-, produced from CHO-SS cells that is currently being evaluated clinically. IFN-, was not associated with any biologically-relevant adverse effects in a series of 10 safety pharmacology experiments, in the Ames mutagenicity test, in the micronucleus test, or in intraarterial, intravenous, paravenous or subcutaneous local tolerance studies. Acute, subacute, subchronic and reproductive toxicity studies performed in cynomolgus monkeys and rats showed a toxicity profile similar to that of human , interferon (IFN-,). Except for the acute (single-dose) toxicology study, all of the other toxicity studies showed evidence for the formation of anti-IFN-, antibodies over time in the animals. These antibodies were found to neutralize IFN-, antiviral activity in vitro in a dose-dependent manner. The average pharmacokinetic parameters following a single subcutaneous dose of IFN-, in rabbits, rats and monkeys were determined and found to be similar to that of human IFN-,. These findings demonstrate that IFN-, has a safety profile consistent with that required for its use in man. IFN-, might be beneficial for the treatment of patients infected with hepatitis C virus who fail to respond to IFN-, or as a first-line treatment option. [source] Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3ABRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2009Sandrine Turpault WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Numerous cocktails using concurrent administration of several cytochrome P450 (CYP) isoform-selective probe drugs have been reported to investigate drug,drug interactions in vivo. , This approach has several advantages: characterize the inhibitory or induction potential of compounds in development toward the CYP enzymes identified in vitro in an in vivo situation, assess several enzymes in the same trial, and have complete in vivo information about potential CYP-based drug interactions. WHAT THIS STUDY ADDS , This study describes a new cocktail containing five probe drugs that has never been published. , This cocktail can be used to test the effects of a new chemical entity on multiple CYP isoforms in a single clinical study: CYP1A2 (caffeine), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A (midazolam) and was designed to overcome potential liabilities of other reported cocktails. AIMS To assess the pharmacokinetics (PK) of selective substrates of CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol) and CYP3A (midazolam) when administered orally and concurrently as a cocktail relative to the drugs administered alone. METHODS This was an open-label, single-dose, randomized, six-treatment six-period six-sequence William's design study with a wash-out of 7 or 14 days. Thirty healthy male subjects received 100 mg caffeine, 100 mg metoprolol, 0.03 mg kg,1 midazolam, 20 mg omeprazole and 10 mg warfarin individually and in combination (cocktail). Poor metabolizers of CYP2C9, 2C19 and 2D6 were excluded. Plasma samples were obtained up to 48 h for caffeine, metoprolol and omeprazole, 12 h for midazolam, 312 h for warfarin and the cocktail. Three different validated liquid chromatography tandem mass spectrometry methods were used. Noncompartmental PK parameters were calculated. Log-transformed Cmax, AUClast and AUC for each analyte were analysed with a linear mixed effects model with fixed term for treatment, sequence and period, and random term for subject within sequence. Point estimates (90% CI) for treatment ratios (individual/cocktail) were computed for each analyte Cmax, AUClast and AUC. RESULTS There was no PK interaction between the probe drugs when administered in combination as a cocktail, relative to the probes administered alone, as the 90% CI of the PK parameters was within the prespecified bioequivalence limits of 0.80, 1.25. CONCLUSION The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug,drug interactions in vivo. [source] Pharmacokinetics, safety, and efficacy of mycophenolate mofetil in combination with sirolimus or ciclosporin in renal transplant patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2007Mark D. Pescovitz Aims To compare the pharmacokinetics of mycophenolic acid (MPA) and its metabolite (MPAG) when mycophenolate mofetil (MMF) is administered in combination with sirolimus or ciclosporin (CsA) in renal allograft recipients. Safety and efficacy (biopsy-proven acute rejection (BPAR)) were also assessed. Methods Patients (n = 45) were randomized 2 : 1 to receive treatment with sirolimus (n = 30; dosed to maintain trough concentrations of 10,25 ng ml,1 until week 8, and then 8,15 ng ml,1 thereafter) or CsA (n = 15; administered as per centre practice) both in combination with daclizumab, oral MMF and corticosteroids. Pharmacokinetic assessments were performed at day 7, week 4, and months 3 and 6 post-transplant. The primary endpoint was the AUC(0,12 h) for MPA and MPAG. The pharmacokinetics of sirolimus were also assessed. Results MPA exposure was 39,50% lower (month 6 mean AUC(0,12 h) (95%CI): 40.4 (33.8, 47.0) vs. 68.5 (54.9, 82.0) µg ml,1 h) and MPAG exposure was 25,52% higher (722 (607, 838) vs. 485 (402, 569) µg ml,1 h at month 6) in the presence of CsA compared with sirolimus across visits. BPAR was 40.0% with sirolimus and 13.3% with CsA. The incidence of hypertension, tremors and hirsutism was higher with CsA than with sirolimus, while the incidence of diarrhoea, hyperlipidaemia and impaired wound closure was higher with sirolimus. No deaths, malignancies or graft losses were reported. Conclusions Co-administration of sirolimus with MMF led to greater MPA exposure, but lower MPAG exposure, than co-administration with CsA. As rejection rates were higher in the absence of CsA, further study of calcineurin inhibitor-free regimens is required before general recommendations can be made. [source] Pharmacokinetic Interaction of the Direct Renin Inhibitor Aliskiren with Furosemide and Extended-Release Isosorbide-5-Mononitrate in Healthy SubjectsCARDIOVASCULAR THERAPEUTICS, Issue 4 2008Sujata Vaidyanathan This study investigated the pharmacokinetics, safety, and tolerability of aliskiren administered alone or in combination with either the loop diuretic furosemide or an oral extended-release formulation of isosorbide-5-mononitrate (ISMN). In separate studies, 22 healthy subjects (ages 18,45 years) received either ISMN 40 mg or furosemide 20 mg once-daily for 3 days followed by a 3-day washout. Subjects then received aliskiren 300 mg once-daily for 7 days followed by combination therapy for 3 days. Pharmacokinetic assessments were taken at regular intervals over 24 h after dosing on the last day of each treatment period. At steady state, aliskiren AUC, was decreased by 7% (geometric mean ratio [90% CI], 0.93 [0.84, 1.04]), and Cmax by 20% (0.80 [0.65, 0.97]) with furosemide coadministration compared with aliskiren administration alone. Aliskiren coadministration reduced furosemide AUC, by 28% (0.72 [0.64, 0.81]) and Cmax by 49% (0.51 [0.39, 0.66]) compared with furosemide alone. Coadministration of aliskiren and ISMN was associated with only minor changes in the pharmacokinetic parameters of aliskiren (AUC, 1.03 [0.90, 1.18]; Cmax 0.94 [0.69, 1.29]) and ISMN (AUC, 0.88 [0.71, 1.10]; Cmax 0.94 [0.79, 1.13]). Headache and dizziness were the most common adverse events in both studies; dizziness and BP values below normal (SBP <90 and/or DBP <50 mmHg) were more frequent with aliskiren and ISMN coadministration than with either agent alone. Coadministration of aliskiren and ISMN had no clinically relevant effect on either aliskiren or ISMN pharmacokinetics. In conclusion, coadministration of aliskiren and furosemide reduced furosemide exposure and had a minor effect on aliskiren pharmacokinetics. The clinical significance of reduced systemic exposure to furosemide during coadministration of aliskiren is uncertain. [source] Distribution of ifosfamide and metabolites between plasma and erythrocytesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2001T. Kerbusch Abstract The distribution of ifosfamide (IF) and its metabolites 2-dechloroethylifosfamide (2DCE), 3-dechloroethylifosfamide (3DCE), 4-hydroxyifosfamide (4OHIF) and ifosforamide mustard (IFM) between plasma and erythrocytes was examined in vitro and in vivo. In vitro distribution was investigated by incubating blood with various concentrations of IF and its metabolites. In vivo distribution of IF, 2DCE, 3DCE and 4OHIF was determined in 7 patients receiving 9 g/m2/72 h intravenous continuous IF infusion. In vitro distribution equilibrium between erythrocytes and plasma was obtained quickly after drug addition. Mean (±sem) in vitro and in vivo erythrocyte (e),plasma (p) partition coefficients (Pe/p) were 0.75±0.01 and 0.81±0.03, 0.62±0.09 and 0.73±0.05, 0.76±0.10 and 0.93±0.05 and 1.38±0.04 and 0.98±0.09 for IF, 2DCE, 3DCE and 4OHIF, respectively. These ratios were independent of concentration and unaltered with time. The ratios of the area under the erythrocyte and plasma concentration--time curves (AUCe/p) were 0.96±0.03, 0.87±0.07, 0.98±0.06 and 1.34±0.39, respectively. A time- and concentration-dependent distribution--equilibrium phenomenon was observed with the relative hydrophilic IFM. It is concluded that IF and metabolites rapidly reach distribution equilibrium between erythrocytes and plasma; the process is slower for IFM. Drug distribution to the erythrocyte fraction ranged from about 38% for 2DCE to 58% for 4OHIF, and was stable over a wide range of clinically relevant concentrations. A strong parallelism in the erythrocyte and plasma concentration profiles was observed for all compounds. Thus, pharmacokinetic assessment using only plasma sampling yields direct and accurate insights into the whole blood kinetics of IF and metabolites and may be used for pharmacokinetic,pharmacodynamic studies. Copyright © 2001 John Wiley & Sons, Ltd. [source] Multiple mealtime administration of biphasic insulin aspart 30 versus traditional basal-bolus human insulin treatment in patients with type 1 diabetesDIABETES OBESITY & METABOLISM, Issue 6 2006J. -W. Aim:, The aim of this study was to compare the effect of multiple mealtime injections of biphasic insulin aspart 30 (30% fast-acting insulin aspart in the formulation, BIAsp30) to traditional basal-bolus human insulin regimen (HI) on glycaemic control in patients with type 1 diabetes. Methods:, Twenty-three patients (eight women and 15 men) aged 44.8 (20.6,62.5) years (median and range) with a diabetes duration of 19.5 (1.6,44.6) years completed the study. All eligible patients were randomly assigned to BIAsp30 thrice daily supplied with bedtime NPH insulin when necessary, or basal-bolus HI for 12 weeks and then switched to the alternative regimen for another 12 weeks. The insulin dose adjustments were made by patients on the basis of advice from a diabetes nurse. At end of each treatment period, the patients attended two profile days, 1 week apart for pharmacodynamic and pharmacokinetic assessments. HbA1C was measured at baseline and at the end of each treatment period. A seven-point self-monitored blood glucose (SMBG) was obtained twice weekly. Results:, In comparison with HI, multiple mealtime injections of BIAsp30 resulted in a significant reduction in HbA1C[HI vs. BIAsp30 (%, geometric mean and range): 8.6 (7.4,11.4) vs. 8.3 (6.7,9.8), p = 0.013]. During treatment with BIAsp30, nighttime glycaemic control was significantly improved. Day-to-day variation in pharmacodynamics and pharmacokinetics and the rate of hypoglycaemia were not increased with BIAsp30 compared with HI. Conclusions:, In type 1 diabetics, multiple mealtime administration of BIAsp30 compared with traditional basal-bolus human insulin treatment significantly improves long-term glycaemic control without increasing the risk of hypoglycaemia. Despite a higher proportion of intermediate-acting insulin, thrice-daily injections with BIAsp30 do not increase the day-to-day variations in insulin pharmacokinetics and pharmacodynamics. [source] | ||||||||||