Population pharmacokinetics of edoxaban in patients with symptomatic deep‐vein thrombosis and/or pulmonary embolism—the Hokusai‐VTE phase 3 study

AimsThis study characterized the population pharmacokinetics of edoxaban in patients with symptomatic deep‐vein thrombosis and/or pulmonary embolism in the Hokusai‐VTE phase 3 study. The impact of the protocol‐specified 50% dose reductions applied to patients with body weight ≤ 60 kg, creatinine clearance (CL_cr) of 30 to 50 ml min^–1 or concomitant P‐glycoprotein inhibitor on edoxaban exposure was assessed using simulations.MethodsThe sparse data from Hokusai‐VTE, 9531 concentrations collected from 3707 patients, were pooled with data from 13 phase 1 studies. In the analysis, the covariate relationships used for dose reductions were estimated and differences between healthy subjects and patients as well as additional covariate effects of age, race and gender were explored based on statistical and clinical significance.ResultsA linear two‐compartment model with first order absorption preceded by a lag time best described the data. Allometrically scaled body weight was included on disposition parameters. Apparent clearance was parameterized as non‐renal and renal. The latter increased non‐linearly with increasing CL_cr. Compared with healthy volunteers, inter‐compartmental clearance and the CL_cr covariate effect were different in patients (+64.6% and +274%). Asian patients had a 22.6% increased apparent central volume of distribution. The effect of co‐administration of P‐glycoprotein inhibitors seen in phase 1 could not be confirmed in the phase 3 data. Model‐based simulations revealed lower exposure in dose‐reduced compared with non‐dose‐reduced patients.ConclusionsThe adopted dose‐reduction strategy resulted in reduced exposure compared with non‐dose‐reduced, thereby overcompensating for covariate effects. The clinical impact of these differences on safety and efficacy remains to be evaluated.     

Population pharmacokinetics of tipifarnib in healthy subjects and adult cancer patients

AIMS: To characterize the population pharmacokinetics of tipifarnib. METHODS: A total of 1083 subjects treated orally with a solution, capsule or tablet formulations of tipifarnib, given as a single dose or as multiple twice-daily doses (range 25-1300 mg) were combined with data from 1, 2 and 24 h intravenous infusions. A total of 3445 concentrations in the index data set were fitted by an open three-compartment linear disposition model with sequential zero-order input into the depot compartment, followed by a first-order absorption process, and lag time, using NONMEM V. The effect of patient covariates on tipifarnib pharmacokinetics was explored. The model was evaluated using goodness of fit plots and relative error measurements for 3894 concentrations in the test data set. Computer simulations were undertaken to evaluate the effect of covariates on tipifarnib pharmacokinetics. RESULTS: Tipifarnib oral bioavailability (26.7%) did not differ between the formulations. The absorption rate from the solution was faster than from the solid forms. Whereas the absorption rate and systemic clearance were more rapid in healthy subjects, the extent of absorption and the steady-state volume of distribution were comparable in cancer patients and healthy subjects. Systemic clearance in cancer patients (21.9 l h-1) exhibited a statistically significant relationship with total bilirubin. The typical volume of the central compartment in cancer patients (54.6 l 70 kg-1) was directly proportional to body weight. The clinical relevance of these covariates in cancer patients is questionable as there was a substantial overlap in simulated concentration-time profiles across a wide range of covariate values. CONCLUSIONS: A population PK approach has been used to integrate data gathered during clinical development and to characterize the pharmacokinetics of tipifarnib. Individualization of dose based on body weight or total bilirubin concentration in adult cancer patients is not warranted.     

Population pharmacokinetics of deferiprone in healthy subjects

Aims

To characterize the pharmacokinetics of deferiprone in healthy subjects using a model-based approach and to assess the effect of demographic and physiological factors on drug exposure.

Methods

Data from 55 adult healthy subjects receiving deferiprone (solution 100 mg ml⁻¹) were used for model building purposes. A population pharmacokinetic analysis was performed using nonmem v.7.2. The contribution of gender, age, weight and creatinine clearance (CL_cr) on drug disposition was evaluated according to standard forward inclusion, backward deletion procedures. Model selection criteria were based on graphical and statistical summaries.

Results

A one compartment model with first order oral absorption was found to describe best the pharmacokinetics of deferiprone. Simulated exposure values were comparable with previously published data. Mean AUC estimates were 45.8 and 137.4 mg l⁻¹ h, whereas C_max increased from 17.6 to 26.5 mg l⁻¹ after administration of 25 and 75 mg kg⁻¹ doses, respectively. Gender differences in the apparent volume of distribution (20%) have been identified, which are unlikely to be of clinical relevance. Furthermore, simulation scenarios reveal that dose adjustment is required for patients with reduced CL_cr. Doses of 60, 40 and 25 mg kg⁻¹ for patients showing mild, moderate and severe renal impairment are proposed based on CL_cr values of 60–89, 30–59 and 15–29 ml min⁻¹, respectively.

Conclusions

Our analysis has enabled the assessment of the impact of gender and CL_cr on the pharmacokinetics of deferiprone. Moreover, it provides the basis for dosing recommendations in renal impairment. The implication of these covariates on systemic exposure is currently not available in the prescribing information of deferiprone.     

头孢克肟在中国健康男性志愿者的群体药代动力学研究

目的考察中国健康男性志愿者单剂量口服头孢克肟200mg后的对群体药代动力学参数影响的因素,为个体化给药提供依据。方法 74名中国健康男性志愿者于试验前一天吃清淡晚餐后收住在北大医院Ⅰ期病房,禁食 12h,受试当天早晨空腹用250mL温开水送服不同产地、不同剂型的头孢克肟制剂(含头孢克肟200mg),血清中头孢克肟的浓度采用反相HPLC-UV法测定,用NONMEM软件评价74名中国健康男性志愿者单剂量口服 200mg不同剂型头孢克肟后的群体药代动力学。结果药物剂型、生产厂家对清除率有显著影响(P<0．001), 药物产地,肾功能(Urea)对表观分布容积有显著影响(P<0．001)。结论临床应用头孢克肟时,可根据肾功能调节用药剂量。同时应注意厂家和剂型,仔细阅读该厂的说明书,注意药代动力学参数的差别。     

Tadalafil pharmacokinetics in healthy subjects

AIMS: To characterize tadalafil plasma pharmacokinetics in healthy subjects following single and multiple doses. METHODS: Noncompartmental parameters were calculated for healthy subjects receiving a single 2.5-20-mg tadalafil dose in 13 clinical pharmacology studies. An integrated statistical analysis of results in 237 subjects provided global averages and an assessment of effects of body mass index (BMI), age, gender and smoking status. Diurnal variation, food effects and proportionality of exposure to dose were analysed in three studies. Multiple-dose pharmacokinetics were evaluated in a separate study in which parallel groups of 15 subjects received 10 or 20 mg tadalafil once daily for 10 days. RESULTS: Tadalafil was absorbed rapidly with mean Cmax (378 microg l-1 for 20 mg) observed at 2 h; thereafter, concentrations declined nearly monoexponentially with a mean (5th, 95th percentiles) t1/2 of 17.5 (11.5, 29.6) hours. Mean oral clearance (CL/F) was 2.48 (1.35, 4.35) l h-1 and apparent volume of distribution (Vz/F) was 62.6 (39.5, 92.1) l. No clinically meaningful effect of BMI, age, gender or smoking was identified. Exposure was not substantially affected by time of dosing. Food had negligible effects on bioavailability as assessed by 90% confidence intervals for Cmax and AUC mean ratios. Parameters were proportional to dose, indicating that doubling the dose doubled exposure. Steady state was attained by day 5 following once-daily administration, and accumulation (1.6-fold) was consistent with the t1/2. CONCLUSIONS: Tadalafil pharmacokinetics are linear with respect to dose and time, and are not affected by food. Systemic clearance is low relative to other phosphodiesterase 5 inhibitors.     

Population pharmacokinetics of pregabalin in healthy subjects and patients with post-herpetic neuralgia or diabetic peripheral neuropathy

AIM

Pregabalin, a chemical analogue of the mammalian neurotransmitter γ-aminobutyric acid, has been approved in many countries for partial-onset seizures, generalized anxiety disorder and various other pain disorders, including neuropathic pain associated with post-herpetic neuralgia and diabetic peripheral neuropathy and fibromyalgia. The aim of this study was to develop a population pharmacokinetic model and quantify the influence of covariates on the parameters.

METHODS

This pregabalin population pharmacokinetic analysis was conducted on data from 14 clinical trials involving healthy subjects, subjects with impaired renal function and patients with post-herpetic neuralgia or diabetic peripheral neuropathy (n = 616). The data analysis was performed using nonlinear mixed effects modelling methodology as implemented by NONMEM.

RESULTS

A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. The model indicated that pregabalin apparent clearance (CL/F) was proportional to estimated creatinine clearance (CL_cr). The pregabalin systemic exposure in patients with lower renal function who received pregabalin 150 mg twice daily was almost equal to that of patients with normal renal function administered pregabalin 300 mg twice daily. The systemic exposure stratified by lower or normal renal function was similar between patients with post-herpetic neuralgia and diabetic peripheral neuropathy.

CONCLUSION

The developed model identified CL_cr and ideal body weight as clinically influential covariates on CL/F and volume of distribution, respectively. This study indicates that renal function accounts for variability in the apparent clearance of pregabalin which is consistent with what is known about the elimination of this drug.     

Anti-factor Xa kinetics after intravenous enoxaparin in patients undergoing percutaneous coronary intervention: a population model analysis

AIM: Recent studies have suggested that intravenous (i.v.) enoxaparin could be used as antithrombotic therapy in patients ongoing percutaneous coronary intervention (PCI). However, anti-Xa pharmacokinetics following different i.v. dosing regimens is not clearly established. METHODS: A population pharmacokinetic analysis was developed using anti-Xa activities measured in 546 patients who received a single 0.5 mg kg(-1) i.v. dose of enoxaparin immediately before PCI. Effects of higher doses (0.75 mg kg(-1) and 1 mg kg(-1)) and/or additional bolus after the initial administration were similarly simulated. RESULTS: Enoxaparin anti-Xa time profiles were best described by a one-compartment model with zero-order kinetics. Mean population parameters (intersubject variability, %) were CL 1.2 l h(-1) (33), V 2.9 l (30) and zero-order input 0.25 h (24). With a single bolus of 0.5 mg kg(-1), the totality of the patients reached an effective anticoagulation level (anti-Xa >0.5 IU ml(-1)) and only 2.5% reached levels above 1.5 IU ml(-1). Simulations showed that greater doses (0.75 mg kg(-1) and 1 mg kg(-1)) prolonged the duration of anticoagulation (3.4 and 4.1 h, respectively) compared with the 0.5 mg kg(-1) bolus (2.7 h) and markedly increased the proportion (48% and 79%, respectively) of patients with anti-Xa levels >1.5 IU ml(-1). For delayed and/or prolonged procedures, patients could be administered a second bolus of half the initial dose in a time interval between 90 min to 2 h after in order to maintain similar anticoagulation profile levels. CONCLUSIONS: A single 0.5 mg kg(-1) i.v. dose of enoxaparin reached anticoagulation levels adequately and should be safer compared with greater doses for anticoagulation in patients undergoing an elective PCI. An additional second bolus could be proposed in patients with delayed or prolonged procedures.     

Stereoselective pharmacokinetics of tocainide in human uraemic patients and in healthy subjects

Summary The disposition of tocainide enantiomers were examined in healthy human subjects and uraemic patients following a single i. v. dose (200 mg) of racemic tocainide hydrochloride.In the healthy subjects, the total body clearance of R(–)-tocainide was significantly greater than that of S(+)-tocainide (2.62 vs 1.70 ml·min^–1·kg^–1). Renal clearance also favoured R(–)-tocainide and appeared to contribute significantly to the stereoselective total body clearance. The volume of distribution of the enantiomers did not differ significantly.Uraemia produced a marked decrease in the total body clearance with no apparent effect on the volume of distribution of both enantiomers. The S/R ratio for total body clearance decreased significantly from 0.66 in healthy subjects to 0.54 in the uraemics, while the ratio for terminal elimination half-life significantly increased from 1.43 to 1.59.These results indicate that uraemia alters the degree of stereoselectivity in the pharmacokinetic parameters of tocainide enantiomers.     

Population pharmacokinetics of tolvaptan in healthy subjects and patients with hyponatremia secondary to congestive heart failure or hepatic cirrhosis

Tolvaptan is a selective V₂‐receptor antagonist used to treat hypervolemic and euvolemic hyponatremia. A population pharmacokinetic (PK) analysis was performed for tolvaptan in NONMEM® based upon data obtained from three trials conducted in 93 healthy subjects and six trials conducted in 628 congestive heart failure (CHF) patients or 24 hepatic cirrhosis patients receiving oral tolvaptan (5 to 240 mg). A two‐compartment model with first‐order absorption and elimination best described tolvaptan PK. Relative oral bioavailability was modeled relative to 100% for a 30 mg dose and ranged from 79.4% to 122%. Body weight and the impact of CHF or hepatic cirrhosis relative to healthy subjects were statistically significant (p < 0.001) predictors of both the apparent oral clearance (CL/F) and apparent central volume of distribution (V_c/F). The CL/F was reduced to 58.2% for New York Heart Association (NYHA) Class 1 or 2 CHF, 45.5% for NYHA Class 3 or 4 CHF, and 58.0% for hepatic cirrhosis relative to healthy subjects. V_c/F was reduced to 59.9% for NYHA Class 1 or 2 CHF and 51.3% for NYHA Class 3 or 4 CHF, and was 64.8% larger for severe hepatic cirrhosis (Child‐Pugh score ≥ 10) relative to healthy subjects. A slight additional decrease in CL/F of 18.3% was also detected for patients with moderate hyponatremia (serum sodium of 115–130 mEq/l) after adjusting for CHF or cirrhosis (p < 0.001). This population PK model enabled assessment of tolvaptan PK with varying degrees of CHF and hepatic cirrhosis with fluid overload and may be used to explore PK‐PD relationships with respect to fluid and electrolyte balance. Copyright © 2013 John Wiley & Sons, Ltd.     

Population pharmacokinetics of onercept in healthy subjects

OBJECTIVE: To develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics of onercept (recombinant human tumour necrosis factor [TNF] receptor-1) in healthy subjects. SUBJECTS AND METHODS: Onercept pharmacokinetics data were obtained from 48 healthy male and female subjects (four phase I studies). In study A, 12 subjects received increasing single intravenous doses of onercept either 5 and 50mg or 15 and 150mg. In study B, 12 subjects received single intravenous, subcutaneous and intramuscular doses of onercept 50mg. Study C investigated the pharmacokinetics of onercept following repeat subcutaneous administration of six doses of 50mg every 48 hours in 12 subjects. Study D investigated the pharmacokinetics of onercept following repeat subcutaneous administration of six doses of 100mg and 150mg over 2 weeks in 12 subjects. Nonlinear mixed-effects modelling software NONMEM was used to build a base model, while the final model was determined after selection of the covariates. RESULTS: The disposition of onercept was described using a two-compartment model with two absorption processes (a first-order followed by a zero-order) and included a constant baseline, accounting for the endogenous TNF receptor-1 levels. Slow absorption of onercept following subcutaneous and intramuscular administration was observed and suggested that absorption was the rate-limiting process. The population mean (coefficient of variation %) values for clearance, absorption rate constant, volume of distribution of the central compartment, bioavailability of onercept and baseline TNF receptor-1 levels were 4.03 L/h (13.3%), 0.04 h-1 (29.1%), 4.42L (6.2%), 0.90 (23.8%) and 1.68 microg/L (20.4%), respectively. The only significant covariates were found to be dose (which affected clearance), and day (which affected absorption rate constant); however, the effects were small (10-15%) and are unlikely to be of any clinical relevance. CONCLUSION: The proposed population pharmacokinetic model characterises well the overall pharmacokinetic profile of onercept after intramuscular, subcutaneous and intravenous administration in healthy subjects. The pharmacokinetics of onercept showed modest intersubject variability.     

The pharmacokinetics of lamivudine in healthy Chinese subjects

AIMS: The purpose of this study was to investigate the pharmacokinetics of daily oral doses of lamivudine administered to healthy Chinese subjects for 1 week. METHODS: Twenty-four subjects were enrolled, 12 males and 12 females, all between the ages of 18 and 40 years. After an overnight fast, all subjects received a single oral dose of 100 mg lamivudine. Blood was obtained before lamivudine administration and at regular intervals to 24 h post dose. Subsequent doses were given once daily for a total of 7 days. On the last day another full pharmacokinetic profile was obtained to 24 h postdose. Timed urine collections were performed for all subjects on day 1 only. Pharmacokinetic parameters were calculated by using standard non compartmental techniques. RESULTS: Lamivudine was well absorbed in all subjects (tmax 1 h). On day 1 and day 7 the overall geometric mean Cmax was 1304 and 1385 ng ml-1, and AUC(0,24h) was 4357 and 4353 ng ml-1 h, respectively. On average 78% of the lamivudine dose was recovered in urine as parent compound. Pharmacokinetic parameters were very similar between male and female subjects, between day 1 and day 7 and in comparison with data obtained in many other pharmacokinetic studies. CONCLUSIONS: This study demonstrated that the pharmacokinetics of lamivudine are essentially identical between Chinese and Caucasian subjects, and between males and females. It confirms 100 mg lamivudine is an appropriate dose for use in Chinese patients, providing adequate exposure for optimal antiviral effect.     

Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects

Aims

This study investigated the effect of a fixed dose combination of lopinavir/ritonavir on the pharmacokinetics (PK) of selexipag and its active metabolite ACT-333679.

Methods

This was an open label, randomized, single centre, two way, crossover study. Twenty healthy male subjects were treated with a single dose of 400 µg selexipag alone and in combination with multiple doses of lopinavir/ritonavir (400/100 mg) twice daily.

Results

The results showed that lopinavir/ritonavir approximately doubled the exposure to selexipag. The area under the plasma concentration–time curve from time zero to infinity (AUC(0,∞) and the maximum plasma concentration (C_max) of selexipag were 2.2- and 2.1-fold higher, respectively, than under selexipag alone, with a 90% confidence interval (CI) of the geometric mean ratio (GMR) of 1.9, 2.7 and 1.7, 2.6, respectively. For ACT-333679, the clinically more relevant component of selexipag, systemic exposure was increased by 8% (GMR of AUC(0,∞) 1.1, 90% CI 0.9, 1.3), when lopinavir/ritonavir was co-administered with selexipag.The most frequently reported adverse event (AE) was headache. A single dose of selexipag, administered either alone or together with multiple doses of lopinavir/ritonavir, was safe and well tolerated.

Conclusions

Lopinavir/ritonavir does not affect the PK parameters of selexipag and ACT-333679 to a clinically relevant extent. Therefore, adaptation of the selexipag dose is not required when co-administered with inhibitors of the organic anion-transporting polypeptide (OATP) 1B1/ 1B3, P-glycoprotein (P-gp) and/or CYP3A4.     

Integrated pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects

AIM

The aim of the study was to report the first thorough characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of epoprostenol in an integrated manner.

METHOD

Twenty healthy male subjects received two formulations of i.v. epoprostenol, in a crossover design, in sequential infusions of 2, 4, 6 and 8 ng kg⁻¹ min⁻¹ for 2 h each. A sensitive assay was developed which allowed accurate PK characterization of epoprostenol via analysis of the concentration–time profiles of its two primary metabolites, 6-keto-prostacyclin F_1α and 6,15-diketo-13,14-dihydro-prostacyclin F_1α. PD parameters included cardiac output (CO), cardiac index (CIn) and heart rate (HR).

RESULTS

The pharmacokinetics of epoprostenol deviated slightly from dose-proportionality, probably due to a food effect. After infusion of the two formulations of epoprostenol, the t_1/2 values expressed as geometric mean (95% confidence interval) were 0.25 h (0.14, 0.46) and 0.22 h (0.13, 0.38) for 6-keto-prostacyclin F_1α, and 0.32 h (0.22, 0.45) and 0.34 h (0.26, 0.46) for 6,15-diketo-13,14-dihydro-prostacyclin F_1α. A single compartment infusion model with first order elimination adequately described the PK of 6-keto-prostacyclin F_1α. This model also characterized the food effect. Stepwise infusions with epoprostenol resulted in a progressive increase in CO, CIn and HR.

CONCLUSION

Of the two metabolites analyzed, the appearance of 6-keto-prostacyclin F_1α in plasma was more closely associated with the haemodynamic effects of i.v. epoprostenol. PK and PD profiles showed that CIn relates proportionally and linearly to the plasma concentrations of 6-keto-prostacyclin F_1α. These results suggest that 6-keto-prostacyclin F_1α is a suitable surrogate marker of plasma concentrations of epoprostenol.     

Fluvoxamine pharmacokinetics in healthy elderly subjects and elderly patients with chronic heart failure

AIMS

To investigate the effects of age and chronic heart failure (CHF) on the oral disposition kinetics of fluvoxamine.

METHODS

A single fluvoxamine dose (50 mg) was administered orally to 10 healthy young adults, 10 healthy elderly subjects and 10 elderly patients with CHF. Fluvoxamine concentration in plasma was measured for up to 96 h.

RESULTS

With the exception of apparent distribution volume, ageing modified all main pharmacokinetic parameters of fluvoxamine. Thus, peak concentration was about doubled {31 ± 19 vs. 15 ± 9 ng ml⁻¹; difference [95% confidence interval (CI)] 16 (3, 29), P < 0.05}, and area under the concentration–time curve was almost three times higher [885 ± 560 vs. 304 ± 84 ng h ml⁻¹; difference (95% CI) 581 (205, 957), P < 0.05]; half-life was prolonged by 63% [21.1 ± 6.2 vs. 12.9 ± 6.4 h; difference (95% CI) 8.2 (2.3, 14.1), P < 0.01], and oral clearance was halved (1.12 ± 0.77 vs. 2.25 ± 0.66 l h⁻¹ kg⁻¹; difference (95% CI) −1.13 (−1.80, −0.46), P < 0.001]. A significant inverse correlation was consistently observed between age and oral clearance (r=−0.67; P < 0.001). The coexistence of CHF had no significant effect on any pharmacokinetic parameters in elderly subjects.

CONCLUSIONS

Ageing results in considerable impairment of fluvoxamine disposition, whereas CHF causes no significant modifications. Therefore, adjustment of initial dose and subsequent dose titrations may be required in elderly subjects, whereas no further dose reduction is necessary in elderly patients with CHF.     

A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects

AIM

Aflibercept (VEGF-Trap), a novel anti-angiogenic agent that binds to VEGF, has been investigated for the treatment of cancer. The aim of this study was to develop a mechanism-based pharmacokinetic (PK) model for aflibercept to characterize its binding to VEGF and its PK properties in healthy subjects.

METHODS

Data from two phase I clinical studies with aflibercept administered as a single intravenous infusion were included in the analysis. Free and bound aflibercept concentration−time data were analysed using a nonlinear mixed-effects modelling approach with MONOLIX 3.1.

RESULTS

The best structural model involved two compartments for free aflibercept and one for bound aflibercept, with a Michaelis–Menten type binding of free aflibercept to VEGF from the peripheral compartment. The typical estimated clearances for free and bound aflibercept were 0.88 l day⁻¹ and 0.14 l day⁻¹, respectively. The central volume of distribution of free aflibercept was 4.94 l. The maximum binding capacity was 0.99 mg day⁻¹ and the concentration of aflibercept corresponding to half of maximum binding capacity was 2.91 µg ml⁻¹. Interindividual variability of model parameters was moderate, ranging from 13.6% (V_max) to 49.8% (Q).

CONCLUSION

The present PK model for aflibercept adequately characterizes the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF.     

来氟米特在中国健康人群中的群体药动学研究

目的：建立来氟米特口服给药在中国健康受试者体内的群体药动学模型,探讨其药动学特征及可能的影响因素。方法：21名健康男性受试者参与本次研究,应用Phoenix NLME（Vision 8.0）软件中的群体模块分析来氟米特口服给药后其代谢产物的血药浓度数据,估算相关药动学参数及其变异情况。结果：来氟米特活性代谢产物特立氟胺在健康志愿者中符合一级吸收的一室模型。吸收速率常数K_a、分布容积V、药物清除率CL的群体典型值分别为0.691 h^-1、12.843 L和0.031 L·h^-1。协变量筛选结果显示,BMI对分布容积V有显著影响（P<0.01）。结论：本研究成功建立了来氟米特在中国健康人群中的群体药动学模型,最终模型可对个体药代参数做出精确的估计,BMI对分布容积V有显著影响。     

阿托伐他汀在健康受试者中的群体药动学研究

目的建立阿托伐他汀在健康受试者中的群体药动学模型,预测其在健康人群中群体药动学特征,为临床合理用药提供依据。方法计算机检索中国期刊全文数据库(CNKI)、中文科技期刊全文数据库维普(VIP)和万方数字化期刊全文库、Pub Med电子检索系统和美国医学文摘数据库(Medline),提取阿托伐他汀的血药浓度数据,运用非线性混合效应模型(NONMEM)法构建阿托伐他汀的群体药动学模型,考察其在健康受试者体内的群体典型值特征,并以Bootstrap法进行模型验证。结果筛选出11篇文献,共纳入394例受试群体。最终得到的群体药动学参数中表观清除率(Cl/F)和表观分布容积(V/F)的群体典型值分别为255 L/h、3 180 L。结论经Bootstrap验证,阿托伐他汀在健康受试者中的群体药动学模型稳定、可靠,所得参数稳定、可信度较好。     

Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with leflunomide cessation in rheumatoid arthritis

Aim

Leflunomide, via its active metabolite teriflunomide, is used in rheumatoid arthritis (RA) treatment, yet approximately 20 to 40% of patients cease due to toxicity. The aim was to develop a time‐to‐event model describing leflunomide cessation due to toxicity within a clinical cohort and to investigate potential predictors of cessation such as total and free teriflunomide exposure and pharmacogenetic influences.

Methods

This study included individuals enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2000 and 2013 who received leflunomide. A time‐to‐event model in nonmem was used to describe the time until leflunomide cessation and the influence of teriflunomide exposure and pharmacogenetic variants. Random censoring of individuals was simultaneously described. The clinical relevance of significant covariates was visualized via simulation.

Results

Data from 105 patients were analyzed, with 34 ceasing due to toxicity. The baseline dropout hazard and baseline random censoring hazard were best described by step functions changing over discrete time intervals. No statistically significant associations with teriflunomide exposure metrics were identified. Of the screened covariates, carriers of the C allele of CYP1A2 rs762551 had a 2.29 fold increase in cessation hazard compared with non‐carriers (95% CI 2.24, 2.34, P = 0.016).

Conclusions

A time‐to‐event model described the time between leflunomide initiation and cessation due to side effects. The C allele of CYP1A2 rs762551 was linked to increased leflunomide toxicity, while no association with teriflunomide exposure was identified. Future research should continue to investigate exposure–toxicity relationships, as well as potentially toxic metabolites.     

The pharmacokinetics of methadone in healthy subjects and opiate users

Aims There is some evidence that monitoring methadone plasma concentration may be of benefit in dosage adjustment during methadone maintenance therapy for heroin (opiate) dependence. However, the kinetics of oral methadone are incompletely characterized. We attempted to describe the latter using a population approach combining intensive 57 h sampling data from healthy subjects with less intensive sparse 24 h data from opiate users. Methods Single oral doses of rac-methadone were given to 13 drug-naive healthy subjects (7 men and 6 women) and 17 opiate users beginning methadone maintenance therapy (13 men and 4 women). Plasma methadone concentrations were measured by h.p.l.c. Kinetic analysis was performed using the P-Pharm software. Results Comparison of kinetic models incorporating mono- or biexponential disposition functions indicated that the latter best represented the data. The improvement was statistically significant for the data from healthy subjects whether the full 57 h or truncated 24 h profiles were used (P<0.031 and P<0.024, respectively), while it was of borderline significance for the more variable data from opiate users (P=0.057) or for pooled (healthy subjects and opiate users) data (P=0.066). The population mean oral clearance of methadone was 6.9±1.5 s.d. l h⁻¹ (5.3±1.2 s.d. l h⁻¹ using 0–24 h data) in the healthy subjects. The results of separate analyses of the data from opiate users and healthy subjects were in contrast with those obtained from pooled data analysis. The former indicated a significantly lower clearance for opiate users (3.2±0.3 s.d. l h⁻¹, P<0.001); 95% CI for the difference=−3 to −6 l h⁻¹ and no difference in the population mean values of V /F (212±27 s.d. l and 239±121 s.d. l, P=0.15), while according to the latter analysis addiction was a covariate for V /F but not for oral clearance. A slower absorption of methadone in opiate users was indicated from the analysis of both pooled and separate data. The median elimination half-life of methadone in healthy subjects was 33–46 h depending on the method used to calculate this parameter. Conclusions Estimates of the long terminal elimination half-life of methadone (33–46 h in healthy subjects and, possibly, longer in opiate users) indicated that accurate measurement of this parameter requires a duration of sampling longer than that used in this study. Our analysis also suggested that parameters describing plasma concentrations of methadone after a single oral dose in healthy subjects may not be used for predicting and adjusting dosage in opiate users receiving methadone maintenance therapy unless coupled with feedback concentration monitoring techniques (for example Bayesian forecasting).