Coadministration of lansoprazole and naproxen does not affect the pharmacokinetic profile of methotrexate in adult patients with rheumatoid arthritis

Drugs prescribed for rheumatoid arthritis are often associated with gastrointestinal toxicity, and proton pump inhibitors may be coadministered for gastroprotection. In this open-label study, the effect of lansoprazole 30 mg qd and naproxen 500 mg bid on the pharmacokinetic profile of methotrexate was investigated. Twenty-seven adult rheumatoid arthritis patients on stable oral methotrexate doses (7.5-15 mg/week) for a minimum of 3 months were enrolled. Methotrexate pharmacokinetics were assessed on days -1 (methotrexate alone) and 7 (methotrexate with lansoprazole and naproxen). Pharmacokinetics of methotrexate and 7-hydroxymethotrexate were not altered by coadministration of methotrexate with lansoprazole and naproxen; point estimates and 90% confidence intervals for the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries. Therefore, coadministration of naproxen and lansoprazole for 7 days does not affect the pharmacokinetic profile of low doses of methotrexate.     

Unaltered etanercept pharmacokinetics with concurrent methotrexate in patients with rheumatoid arthritis

The purpose of this study was to evaluate the potential impact of concurrent weekly oral methotrexate administration on the pharmacokinetics of etanercept in patients with rheumatoid arthritis (RA) in a phase 3B trial. As part of a double-blind randomized trial of 682 patients with rheumatoid arthritis who received etanercept (25 mg subcutaneously twice weekly), methotrexate (weekly oral dose, median weekly dose: 20 mg), or etanercept (25 mg subcutaneously twice weekly) plus methotrexate (weekly oral dose, median weekly dose: 20 mg), serum etanercept concentrations were measured in a subset of patients. Serum samples for 98 randomly selected patients (48 receiving etanercept-alone treatment, 50 receiving etanercept plus methotrexate combination treatment) were analyzed to assess the pharmacokinetics of etanercept. A single blood sample was drawn from each patient at baseline and at the week 24 visit. Given the variable sampling time for patients in both groups, a population pharmacokinetic analysis using NONMEM was conducted for etanercept. A final covariate population pharmacokinetic model was constructed based on previously obtained etanercept data from both healthy subjects (n = 53) and patients with RA (n = 212) in 10 prior clinical trials. The predictive performance of the final model was assessed by both bootstrap and data-splitting validation approaches. The final model was then used to estimate Bayesian pharmacokinetic parameters for the patients in both treatments in the current trial. The potential effect of the concurrent administration of methotrexate on the pharmacokinetics of etanercept was examined by comparing the clearance values between 2 treatments using statistical criteria. A population 2-compartment model with first-order elimination from the central compartment and with either zero-order (intravenous administration) or first-order (subcutaneous administration) input was selected based on the data from the prior 10 etanercept clinical studies. The following pharmacokinetic parameters (typical value +/- standard error) were estimated: clearance (CL: 0.072 +/- 0.005 L/h), volume of distribution in the central compartment (V(c): 5.97 +/- 0.45 L), volume of distribution in the peripheral compartment (V(p): 2.05 +/- 0.32 L), intercompartment clearance (Q: 0.0645 +/- 0.0093 L/h), first-order absorption rate constant (k(a): 0.0282 +/- 0.0039 1/h), and absolute bioavailability for subcutaneous administration (F: 0.626 +/- 0.056). Interindividual variability of the pharmacokinetic parameters was quantified for CL (25.1%), V(c) (41.7%), k(a) (53.1%), and F (24.2%). Residual variability consisted of combined additive (11.4 ng/mL) and proportional error (49.9%). Both age (< 17 years) and body weight (< 60 kg) were found to be important covariates on CL. The results of both validation tests indicated the adequate predictive performance of the population model. Based on the bioequivalence criteria, the Bayesian-estimated clearance for patients receiving etanercept alone (mean: 0.070 L/h) was comparable to that for patients receiving a combination of etanercept and methotrexate (mean = 0.066 L/h). The pharmacokinetics of etanercept were not altered by the concurrent administration of methotrexate in patients with rheumatoid arthritis. Thus, no etanercept dose adjustment is needed for patients taking concurrent methotrexate.     

雷腾舒治疗甲氨蝶呤反应不足类风湿关节炎患者群体药动学研究

目的:建立群体药代动力学(PPK)模型,探讨群体药代动力参数与有效性和安全性之间的关系.方法:采用非线性混合效应模型,建立雷腾舒的PPK模型,评估PPK对临床的安全性及有效性的影响.结果:模型能较好地拟合雷腾舒的血药浓度,参数估计稳健.研究发现血红蛋白(HBG)水平越高,雷腾舒的清除率越高.药效方面,ACR20与雷腾舒的体内暴露程度显著相关(P<0.05).安全性方面,雷腾舒体内暴露与不良反应、育龄妇女生殖系统不良反应相关性不显著.结论:本研究所建立的群体药动学模型能较好地描述雷腾舒在患者中的药动学特征.雷腾舒的暴露量与ACR20相关性显著、与生殖系统不良反应呈现一定相关性.     

Population pharmacokinetics of zileution,a selective 5-lipoxygenase inhibitor,in patients with rheumatoid arthritis

The pharmacokinetics of zileuton, a novel selective 5-lipoxygenase inhibitor, were studied in 37 patients with rheumatoid arthritis after administration of 200 mg, 400 mg, and 600 mg zileuton for 4 weeks. Patients had 6-h pharmacokinetic evaluation of zileuton on day 14. Plasma zileuton concentrations were quantitated using HPLC. Zileuton pharmacokinetic parameters were estimated using standard noncompartmental methods. A population analysis of zileuton pharmacokinetics was also performed with the NONMEM computer program. The pharmacokinetics of zileuton in patients with rheumatoid arthritis were similar to those previously estimated in normal healthy humans. The peak concentrations and the areas under the curves during the dosing interval were dose proportional. The noncompartmental means of the CL/f, terminal-phase half-life, and V/f of zileuton were approximately 545 ml min^–1, 1.4 h, and 64.3 1, respectively. The estimate of population typical values of the CL/f for a 70-kg person (540 ml min^–1) and V/f for a 70-kg person (64.8 1) from the NONMEM analysis were in agreement with the noncompartmental estimates. Differences in body weight, but not age or gender, helped explain some of the variability in the pharmacokinetics of zileuton in patients. Therefore, there is no pharmacokinetic basis for alteration of the zileuton dose size or the dosing schedule in patients with rheumatoid arthritis.     

Tocilizumab has no clinically relevant effects on methotrexate pharmacokinetics in patients with rheumatoid arthritis

Objective: To assess the effects of tocilizumab on methotrexate and 7-hydroxymethotrexate pharmacokinetics in patients with rheumatoid arthritis and to explore the pharmacodynamic effect of tocilizumab on C-reactive protein (CRP), a marker of inflammation. Methods: Methotrexate (10 - 25 mg) was administered orally on Days 1, 8, 15, 22, 29, 36, and 43. On Day 8 patients received 10 mg/kg tocilizumab intravenously. Blood samples for pharmacokinetic analyses were collected on Days 1, 15, and 43 and for pharmacodynamics (CRP) throughout the study. Results: 90% CIs for mean effect ratios (Day 15/Day 1 and Day 43/Day 1) of methotrexate and 7-hydroxymethotrexate (AUClast and Cmax) were close to or within the bioequivalence boundaries (80 - 125%). CRP normalized within 1 week after tocilizumab injection and remained within normal limits for 3 weeks. Conclusion: Tocilizumab and methotrexate can be administered concurrently without dosage adjustments.     

Monitoring methotrexate therapy in patients with rheumatoid arthritis

OBJECTIVE: The aim of this work was to study methotrexate (MTX) kinetics and their relation to the effectiveness of the therapy in patients with rheumatoid arthritis (RA). Other aims were to analyze the influence of MTX on liver, kidney, hematopoietic function and to determine the possibility of using early drug concentrations to predict the subsequent value of the treatment. MATERIAL AND METHODS: The observations were carried out in 49 patients with RA after the first dose of MTX and after 7 months of treatment. Methotrexate concentrations in blood serum and urine were determined using fluorescence polarization immunoassay applying a TDx Abbott analyzer. RESULTS: No correlation between concentrations, pharmacokinetic parameters and the duration of the disease, its activity, clinical symptoms, observations pertaining to the disease made by physician and patients and morning stiffness of joints was seen. Of those tests for the evaluation of liver, kidney and hematopoietic function, only the mean activity of N-acetyl-beta-D-glucosaminidase (NAG) in urine was significantly elevated both before and after treatment with MTX when compared to corresponding values in the control group of healthy subjects. We have formulated equations allowing for the early recognition of patients with a risk of adverse effects due to impaired elimination of MTX from the body. CONCLUSION: Our results show that monitoring MTX therapy using concentrations in patients with RA does not significantly improve the effectiveness of the treatment, but it can play an important role in increasing the safety of this drug.     

The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis.

1. The pharmacokinetics of MTX and its 7-hydroxy metabolite (7-OHMTX) were investigated in nine patients with rheumatoid arthritis (RA). Each patient received 15 mg MTX i.v., i.m. and p.o. after an overnight fast in a randomized cross-over design. The plasma concentrations of MTX and 7-OHMTX were measured over 7 days and their urinary excretion over 24 h. 2. Plasma concentrations of MTX were described by a triexponential function after i.v. administration, a triexponential function with zero or first order absorption after oral administration, and a biexponential function with zero of first order absorption after i.m. injection. Plasma concentrations of 7-OHMTX were described by a biexponential function after all three routes of administration. The median terminal elimination half-lives of MTX and 7-OHMTX were 55 h and 116 h, respectively. The area under the plasma concentration-time curve (AUC (0,170 h)) of MTX did not differ between i.m. and oral administration indicating similar bioavailability after these routes of administration. The AUC (0,170 h) values of 7-OHMTX after i.v., oral and i.m. administration were similar. Over 80% of MTX was excreted in urine as intact drug and about 3% was excreted as 7-OHMTX during 24 h after drug administration. 3. Plasma concentrations of MTX and 7-OHMTX were measurable at the end of the dose interval in most of the patients and may help to identify non-responders or patients with increased risk of side-effects.     

Risperidone does not affect steady-state pharmacokinetics of divalproex sodium in patients with bipolar disorder

OBJECTIVE: Divalproex sodium can interact with many drugs in which combination treatments are used; it can increase plasma concentrations of some drugs by inhibiting metabolism and can increase the free fractions of other medications by displacing them from plasma proteins. The combination of risperidone and divalproex sodium is used to treat the manic phase of bipolar disorder. However, the effect of risperidone on the pharmacokinetics of valproate has not previously been systematically studied. The aims of this study were to determine the effect of repeated doses of oral risperidone on the pharmacokinetics of valproate in subjects stabilised on divalproex sodium and to document the safety of this combination. STUDY DESIGN: A multicentre, observational, randomised, parallel group, single-blind, placebo-controlled drug interaction study. PATIENTS: Twenty-two patients with bipolar disorder, in remission, were studied. METHODS: All subjects were treated with divalproex sodium 1000 mg/day monotherapy on days 1-14. Thereafter, subjects continued to take divalproex sodium for days 15-28; they also received adjunctive treatment with either placebo (n = 11) or risperidone (n = 11) 2mg once daily on days 15 and 16, and 4 mg once daily on days 17-28. Serial blood sampling was performed throughout to determine the plasma concentrations of valproate, risperidone and 9-hydroxy-risperidone. RESULTS: On analysis, steady-state pharmacokinetic parameters (peak plasma concentrations [C(max)], time to C(max,) area under the concentration-time curve) of valproate were of the same order of magnitude on day 14 (monotherapy) and day 28 (valproate plus risperidone or placebo), with no period effect. The parameters on day 28 were similar in the risperidone and placebo treatment groups, showing that risperidone, as adjunctive treatment, had no influence on the steady-state pharmacokinetics of valproate. Although there were more adverse events reported in the risperidone group compared with the placebo group (ten vs seven, respectively), none of them were serious or necessitated withdrawal. No clinically relevant changes in laboratory parameters, vital signs or ECG-tracings were observed in either group. CONCLUSION: These results indicate that adjunctive risperidone treatment had no influence on the steady-state pharmacokinetics of valproate and this combination was safe and well tolerated.     

Dolutegravir does not affect methadone pharmacokinetics in opioid-dependent,HIV-seronegative subjects

Background

Dolutegravir (DTG) is an investigational integrase inhibitor for treatment of HIV infection. As intravenous drug use is a common risk factor for HIV, this study evaluated the effect of DTG on the pharmacokinetics (PK) of methadone.

Methods

This was an open-label, 2-period study in adult, opioid-dependent, HIV-seronegative subjects. Subjects received their current individual methadone doses once daily for 3 days (Period 1) followed by DTG 50 mg twice daily (BID) for 5 days while continuing their stable methadone therapy (Period 2). Serial PK samples for R- and S-methadone were collected after each Period. Pharmacodynamic (PD) measures and safety assessments were obtained throughout the study. Non-compartmental PK analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated.

Results

Plasma exposures of total, R-, and S-methadone were not affected by co-administration of DTG. Mean ratios for AUC were 0.98, 0.95, and 1.01 for total, R-, and S-methadone, respectively, alone compared with in combination with DTG. No statistically significant differences were noted between the 2 treatment periods in methadone PD measures. The combination of DTG and methadone was well tolerated. No deaths, serious adverse events, or grade 3/4 adverse events occurred. No clinically significant changes in laboratory values, vital signs, or electrocardiograms were observed.

Conclusion

Co-administration of methadone with repeat doses of DTG 50 mg BID had no effect on total, R-, and S-methadone PK or on methadone-induced PD markers. No dose adjustment in methadone is required when given in combination with DTG.     

Salicylate pharmacokinetics in patients with rheumatoid arthritis.

1. The pharmacokinetics of salicylic acid (SA) and its major metabolite salicyluric acid (SU) were studied in nine patients with rheumatoid arthritis following a 900 mg oral dose of acetylsalicylic acid and during 6 weeks of chronic administration of enteric coated aspirin (3,900 mg day). Response to therapy was also monitored. 2. The various pharmacokinetic parameters determined in the study were similar to those observed in other single dose salicylate studies amongst healthy volunteers but were not predictive of salicylate concentration in the chronic dose study. 3. Plasma concentrations of SA (total and unbound) were found to decline significantly over the 6 weeks and plasma SU concentrations increased. 4. During the chronic dosing study, there was a significant increase in the Vmax (total and unbound) for the formation of SU, whilst the Km and SU clearance remained constant. Also, the elimination rate constant (k) for salicylate was not significantly affected. 5. Therapeutic response to salicylate therapy was not significantly affected by the decline in SA concentrations.     

The CYP2C8 inhibitor gemfibrozil does not affect the pharmacokinetics of zafirlukast

Purpose  

Gemfibrozil, a strong inhibitor of cytochrome P450 (CYP) 2C8 in vivo, was recently found to markedly increase the plasma concentrations of montelukast in humans. Like montelukast, zafirlukast is a substrate of CYP2C9 and CYP3A4 and a potent inhibitor of CYP2C8 in vitro. To investigate the contribution of CYP2C8 to the metabolism of zafirlukast in vivo, we studied the effect of gemfibrozil on the pharmacokinetics of zafirlukast.     

Valdecoxib,a COX-2-specific inhibitor,does not affect cardiac repolarization

This double-blind, four-way crossover study assessed the effect of valdecoxib on the QTc interval duration in 25 male and 9 female healthy adults. Subjects received placebo or 40 mg, 80 mg, or 120 mg valdecoxib once daily for 5 days. Serial ECGs were obtained for 24 hours before the first treatment (baseline) and on the 5th day of each treatment. The study was statistically powered to detect a difference of > or = 5.6 ms in the average daily QTc change from baseline and a > or = 7.8-ms difference in the average maximal daily change from baseline. No QTc prolongation versus placebo (Fridericia's or Bazett's correction) was observed for any valdecoxib dose. A 22% greater than proportional increase in valdecoxib AUC0-24 was observed over the 40- to 120-mg dose range, supporting the conclusiveness of the negative QTc risk assessment even at supratherapeutic doses (up to three times the maximum recommended dose of 40 mg per day) and concentrations. In conclusion, repeated administration of doses up to 120 mg valdecoxib had no effect on cardiac repolarization in healthy volunteers, suggesting that chronic administration of valdecoxib to patients would not increase the risk from cardiac arrhythmia associated with QT prolongation.     

Salicyl phenolic glucuronide pharmacokinetics in patients with rheumatoid arthritis

Summary The pharmacokinetics of salicyl phenolic glucuronide (SPG) and other salicylic acid (SA) metabolites were studied at three aspirin dosage regimens in eight patients with rheumatoid arthritis. Each patient received 1, 2 and 4 g enteric coated aspirin (ASA) daily in ascending order. At the end of each 2-week dosage period, plasma and urine were collected over a dosage interval for the estimation of various pharmacokinetic parameters. With increasing ASA dosage, mean clearance of SA to SPG was approximately constant (1.8±0.3, 1.7±0.2, and 1.5±0.2 ml/min at 1, 2 and 4 g/day, respectively) when related to plasma concentrations of total SA. The percentage of the ASA dosage recovered in urine as SPG increased from 5.2±1.1 to 7.1±1.1 to 10.5±1.7 at 1, 2 and 4 g/day, respectively. It was concluded, however, that the conversion of SA to SPG is saturable, since the mean clearance of SA to SPG decreased when calculated with respect of the plasma concentration of unbound SA (13.4±1.6, 11.0±1.4, and 6.6±1.9 ml/min at 1, 2 and 4 g/day, respectively). The kinetics of the formation and excretion of salicylurate and the excretion of gentisate were similar to those found in previous studies.     

Population pharmacokinetics of hydroxychloroquine in patients with rheumatoid arthritis

SUMMARY: Hydroxychloroquine (HCQ) is an antimalarial drug that is also used as a second-line treatment of rheumatoid arthritis (RA). Clinically, the use of HCQ is characterized by a long delay in the onset of action, and withdrawal of treatment is often a result of inefficacy rather than from toxicity. The slow onset of action can be attributed to the pharmacokinetics (PK) of HCQ, and wide interpatient variability is evident. Tentative relationships between concentration and effect have been made, but to date, no population PK model has been developed for HCQ. This study aimed to develop a population PK model including an estimation of the oral bioavailability of HCQ. In addition, the effects of the coadministration of methotrexate on the PK of HCQ were examined. Hydroxychloroquine blood concentration data were combined from previous pharmacokinetic studies in patients with rheumatoid arthritis. A total of 123 patients were studied, giving the data cohort from four previously published studies. Two groups of patients were included: 74 received hydroxychloroquine (HCQ) alone, and 49 received HCQ and methotrexate (MTX). All data analyses were carried out using the NONMEM program. A one-compartment PK model was supported, rather than a three-compartment model as previously published, probably because of the clustering of concentrations taken at the end of a dosing interval. The population estimate of bioavailability of 0.75 (0.07), n = 9, was consistent with literature values. The parameter values from the final model were: Cl = 9.9 +/- 0.4 L/h, V = 605 +/- 91 L, ka = 0.77 +/- 0.22 hours(-1), t(tag) = 0.44 +/- 0.02 hours. Clearance was not affected by the presence of MTX, and, hence, steady-state drug concentrations and maintenance dosage requirements were similar. A population PK model was successfully developed for HCQ.     

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, does not affect the pharmacokinetics of ethinyl estradiol or norethindrone in healthy female subjects

Sitagliptin is a dipeptidyl peptidase-IV (DPP-4) inhibitor used for the treatment of patients with type 2 diabetes mellitus. This randomized, placebo-controlled, 2-period, crossover study evaluated the effect of sitagliptin on the pharmacokinetics of 17 α-ethinyl estradiol (EE(2)) and norethindrone (NET) in healthy female subjects who were receiving oral contraceptives for >3 months prior to enrollment. A total of 18 subjects with normal menstrual cycles received the oral contraceptive pill ORTHO-NOVUM(?) 7/7/7 on days 1 to 28 for 2 successive cycles, and on days 1 to 21 were randomly assigned to receive sitagliptin 200 mg/day (2 × 100 mg tablets) or placebo using a computer-generated allocation schedule. Blood samples for determination of plasma EE(2) and NET concentrations were collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose on day 20 or 21 of each treatment period. The GMRs (90% confidence interval [CI]) for the AUC(0-24 hr) of EE(2) and NET were 0.99 (0.93, 1.06) and 1.03 (0.97, 1.09), respectively, and for C(max) were 0.97 (0.86, 1.10) and 0.98 (0.89, 1.07), respectively. The coadministration of sitagliptin 200 mg/day with an oral contraceptive for 21 days did not lead to clinically meaningful alterations in the pharmacokinetics of EE(2) and NET.     

Temelastine does not affect theophylline pharmacokinetics in normal subjects.

The pharmacokinetics of theophylline (i.v. aminophylline 250 mg) were studied in a balanced, double-blind crossover following the administration of oral temelastine (100 mg) or placebo, twice daily for 7 days, to 10 normal volunteers. Comparison of volumes of distribution, elimination rate constants, elimination half-lives and areas under the plasma concentration-time curve indicated that temelastine had no significant effect on theophylline pharmacokinetics.     

Haemodialysis does not affect the pharmacokinetics of nifedipine.

To establish dosage recommendations in patients with end-stage renal disease undergoing chronic haemodialysis, nifedipine kinetics were studied between and during haemodialysis sessions. In eight patients, during the interdialytic period, peak plasma concentrations of nifedipine (29-332 ng/ml) were reached 0.5-1.0 h after administration of a single 10 mg oral dose. Elimination half-life and oral plasma clearance were respectively 2.6 +/- 0.5 h and 1 176 +/- 412 ml/min. Nifedipine plasma protein binding was decreased in uraemic patients (88.8 +/- 0.3% vs 94.4 +/- 0.1%) but not affected by haemodialysis. Removal by haemodialysis was low: the dialyser extraction ratio and the dialysis clearance were respectively 2.3 +/- 0.8% and 2.8 +/- 0.9 ml/min.