Population pharmacokinetic analysis of tacrolimus in Mexican paediatric renal transplant patients: role of CYP3A5 genotype and formulation

Aims

The aims of this study were (i) to develop a population pharmacokinetic (PK) model of tacrolimus in a Mexican renal transplant paediatric population (n = 53) and (ii) to test the influence of different covariates on its PK properties to facilitate dose individualization.

Methods

Population PK and variability parameters were estimated from whole blood drug concentration profiles obtained at steady-state using the non-linear mixed effect modelling software NONMEM® Version 7.2.

Results

Tacrolimus PK profiles exhibited high inter-patient variability (IPV). A two compartment model with first order input and elimination described the tacrolimus PK profiles in the studied population. The relationship between CYP3A5 genotype and tacrolimus CL/F was included in the final model. CL/F in CYP3A5*1/*1 and *1/*3 carriers was approximately 2- and 1.5-fold higher than in CYP3A5*3/*3 carriers (non-expressers), respectively, and explained almost the entire IPV in CL/F. Other covariates retained in the final model were the tacrolimus dose and formulation type. Limustin® showed markedly lower concentrations than the rest of the formulations.

Conclusions

Population PK modelling of tacrolimus in paediatric renal transplant recipients identified the tacrolimus formulation type as a significant covariate affecting the blood concentrations and confirmed the previously reported significant effect of CYP3A5 genotype on CL/F. It allowed the design of a proposed dosage based on the final model that is expected to help to improve tacrolimus dosing.     

Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients

AIMS

To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate to paediatric patients.

METHODS

Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16–28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids, e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analyzed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM.

RESULTS

A one compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (l h⁻¹) = 11.4 × (WT/70.0)^0.75 and V/F (l) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 l h⁻¹ and 21.4 l, respectively, resulting in an elimination half-life of 11.2 h.

CONCLUSIONS

The range of estimated CL/F in the study population was 0.67–7.38 l h⁻¹. The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients.     

Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients

What is already known about this subject

• In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability.
• Some studies of population pharmacokinetics have already been conducted in liver transplant recipients and in paediatric patients.

What this study adds

• Our work determined population pharmacokinetic parameters, in particular bioavailability, in kidney transplant recipients and the relative importance of factors influencing the disposition of tacrolimus.
• Clearance was modelled and days postoperation and corticosteroids dose were significant covariates.

Aims

The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics.

Methods

The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring.

Results

A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 ± 0.2 l h⁻¹. Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 ± 0.5 days, with a maximal value of 5.6 l h⁻¹. Moreover clearance increased by approximately 1.6 fold (range 0.5–1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 ± 13 l kg⁻¹) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F.

Conclusions

The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.     

Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1

AIMS

To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects.

METHODS

Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol.

RESULTS

A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h⁻¹. The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h⁻¹. Absorption rate constant was estimated at 0.24 h⁻¹ and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed.

CONCLUSIONS

The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol.     

Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit

Aims

The long-term disposition of tacrolimus following kidney transplantation is characterized by a gradual decrease in dose requirements and increase in dose-corrected exposure. This phenomenon has been attributed to a progressive decline in cytochrome P450 3A4 (CYP3A4) activity, although this has never been demonstrated in vivo.

Methods

Sixty-five tacrolimus- and 10 cyclosporine-treated renal transplant recipients underwent pharmacokinetic testing at day 7 and months 1, 3, 6 and 12 after transplantation, including 8-h area under the concentration-time curve (AUC) for tacrolimus or cyclosporine and assessment of CYP3A4 activity using oral and intravenous midazolam (MDZ) drug probes.

Results

Tacrolimus clearance decreased gradually throughout the entire first year but only in CYP3A5*3/*3 homozygous recipients (25.6 ± 11.1 l h^–1 at day 7; 17 ± 9.1 l h^–1 at month 12; P < 0.001). In mixed model analysis, decreasing CYP3A4 activity, measured by apparent oral MDZ clearance (924 ± 443 ml min^–1 at day 7 vs. 730 ± 344 ml min^–1 at month 1; P < 0.001), explained 55.4% of the decline in tacrolimus clearance in the first month. CYP3A4 activity decreased by 18.9 ml min^–1 for every milligram of methylprednisolone dose tapering within the first month; beyond this point it remained stable. A gradual rise in haematocrit throughout the entire first year explained 31.7% of the decrease in tacrolimus clearance in the first month and 23.6% of the decrease between months 1 and 12. Cyclosporine clearance did not change over time.

Conclusions

The maturation of tacrolimus disposition in the first year after renal transplantation observed in CYP3A5*3/*3 homozygous patients can partly be explained by a (steroid tapering-related) decline in CYP3A4 activity and a progressive increase in haematocrit.     

Population pharmacokinetics of mycophenolic acid and dose optimization with limited sampling strategy in liver transplant children

AIMS

The aims were to estimate the mycophenolic acid (MPA) population pharmacokinetic parameters in paediatric liver transplant recipients, to identify the factors affecting MPA pharmacokinetics and to develop a limited sampling strategy to estimate individual MPA AUC(0,12 h).

METHODS

Twenty-eight children, 1.1 to 18.0 years old, received oral mycophenolate mofetil (MMF) therapy combined with either tacrolimus (n= 23) or ciclosporin (n= 5). The population parameters were estimated from a model-building set of 16 intensive pharmacokinetic datasets obtained from 16 children. The data were analyzed by nonlinear mixed effect modelling, using a one compartment model with first order absorption and first order elimination and random effects on the absorption rate (k_a), the apparent volume of distribution (V/F) and apparent clearance (CL/F).

RESULTS

Two covariates, time since transplantation (≤ and >6 months) and age affected MPA pharmacokinetics. k_a, estimated at 1.7 h⁻¹ at age 8.7 years, exhibited large interindividual variability (308%). V/F, estimated at 64.7 l, increased about 2.3 times in children during the immediate post transplantation period. This increase was due to the increase in the unbound MPA fraction caused by the low albumin concentration. CL/F was estimated at 12.7 l h⁻¹. To estimate individual AUC(0,12 h), the pharmacokinetic parameters obtained with the final model, including covariates, were coded in Adapt II® software, using the Bayesian approach. The AUC(0,12 h) estimated from concentrations measured 0, 1 and 4 h after administration of MMF did not differ from reference values.

CONCLUSIONS

This study allowed the estimation of the population pharmacokinetic MPA parameters. A simple sampling procedure is suggested to help to optimize pediatric patient care.     

Prediction of tacrolimus metabolism and dosage requirements based on CYP3A4 phenotype and CYP3A5*3 genotype in Chinese renal transplant recipients

Aim:

To examine how the endogenous CYP3A4 phenotype and CYP3A5^*3 genotype of Chinese renal transplant recipients influenced the dose-corrected trough concentration (C₀/D) and weight-corrected daily dose (D/W) of tacrolimus.

Methods:

A total of 101 medically stable kidney transplant recipients were enrolled, and their blood and urine samples were gathered. The endogenous CYP3A4 phenotype was assessed by the ratio of 6β-hydroxycortisol and 6β-hydroxycortisone to cortisol and cortisone in urine. CYP3A5^*3 genotype was determined using PCR-RELP.

Results:

In overall renal transplant recipients, a multiple regression analysis including the endogenous CYP3A4 phenotype, CYP3A5^*3 genotype and post-operative period accounted for 60.1% of the variability in C₀/D ratio; a regression equation consisting of the endogenous CYP3A4 phenotype, post-operative period, body mass index, CYP3A5^*3 genotype, gender, total bilirubin and age explained 61.0% of the variability in D/W ratio. In CYP3A5^*3/^*3 subjects, a combination of the endogenous CYP3A4 phenotype, post-operative period and age was responsible for 65.3% of the variability in C₀/D ratio; a predictive equation including the endogenous CYP3A4 phenotype, post-operative period, body mass index, gender and age explained 61.2% of the variability in the D/W ratio. Base on desired target range of tacrolimus trough concentrations, individual daily dosage regimen was calculated, and all the observed daily doses were within the predicted range.

Conclusion:

This study provides the equations to predict tacrolimus metabolism and dosage requirements based on the endogenous CYP3A4 phenotype, CYP3A5^*3 genotype and other non-genetic variables.     

Effects of CYP2C9*1/*13 on the pharmacokinetics and pharmacodynamics of meloxicam

AIMS

To determine the effects of the CYP2C9*1/*13 genotype on the pharmacokinetics and pharmacodynamics of meloxicam in Korean subjects.

METHODS

Meloxicam (15 mg) was orally administered to 21 healthy Korean volunteers with either the CYP2C9*1/*1 or the CYP2C9*1/*13 genotype. Plasma meloxicam concentrations were analysed by HPLC-UV for 72 h after drug administration. The pharmacodynamic effects of meloxicam were determined by measuring TXB₂ generated in blood.

RESULTS

The AUC(0,∞) and C_max of meloxicam were 2.43- and 1.46-fold higher in the CYP2C9*1/*13 group than in the CYP2C9*1/*1 group, respectively. The oral clearance of meloxicam was significantly lower in the CYP2C9*1/*13 group (37.9% of wild type) than in the CYP2C9*1/*1 group. The t_1/2 of meloxicam was 1.84-fold longer in the CYP2C9*1/*13 group than in the CYP2C9*1/*1 group. The rate of TXB₂ production was significantly lower in the CYP2C9*1/*13 group than in the CYP2C9*1/*1 group.

CONCLUSIONS

The CYP2C9*1/*13 genotype is associated with decreased metabolism and increased pharmacodynamic effects of meloxicam.     

Effect of anti-tuberculosis therapy on polymorphic drug metabolizing enzyme CYP2C9 using phenytoin as a probe drug

Objectives:

Patients on anti-tuberculosis therapy (ATT) are more prone to drug interactions in the presence of coexisting illnesses which warrant drug therapy. Rifampicin is a strong CYP enzyme inducer while isoniazid is a potent CYP inhibitor. The objective of the study was to find the net effect of one month ATT on CYP2C9 enzyme and to correlate it with respect to the CYP2C9 genetic polymorphisms.

Materials and Methods:

Forty eight newly diagnosed tuberculosis patients were included in the study based on the inclusion-exclusion criteria. Before commencing ATT, they were given a single dose of phenytoin 300 mg as a probe drug for CYP2C9. Blood sample was collected after three hours to carry out CYP2C9 genotyping by PCR-RFLP method. Phenotyping for CYP2C9 enzyme was done by measuring the ratio of phenytoin and its metabolite p-HPPH (para hydroxy phenyl hydantoin) by reverse phase HPLC (high performance liquid chromatography) method before and after one month of ATT.

Results:

In the CYP2C9*1*1 genotype, the mean plasma concentrations of phenytoin before and after one month of ATT were 5.2 ± 0.3 μg/ml and 3.5 ± 0.4 μg/ml respectively, a reduction by 33% showing significant induction (P < 0.001). There was also significant decrease in the metabolic ratio after one month of ATT from 23.2 ± 4.8 to 10.1 ± 1.9 (P < 0.001). The metabolic ratio was also observed to reduce significantly (P < 0.05) when the CYP2C9*1*2, CYP2C9*1*3, and CYP2C9*3*3 data were pooled together.

Conclusion:

The presence of polymorphisms in the CYP2C9 gene does not affect the induction potential of ATT.KEY WORDS: Anti-tuberculosis therapy, CYP2C9, induction, inhibition, pharmacogenetics     

Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients

Aim:

To evaluate the pharmacokinetics of tacrolimus in Chinese stable liver transplant recipients converted from immediate release (IR) tacrolimus-based immunosuppression to modified release (MR) tacrolimus-based immunosuppression.

Methods:

Open-label, multi-center study with a one-way conversion design was conducted. Eighty-three stable liver recipients (6–24 months post-transplant) with normal renal and stable hepatic function were converted from IR tacrolimus twice-daily treatment to MR tacrolimus once-daily treatment on a 1:1 (mg: mg) total daily dose basis. Twenty-four hour pharmacokinetic studies were carried out on d 0 (pre-conversion), d 1, and d 84 (post-conversion).

Results:

The area under the blood concentration–time curve of MR tacrolimus from 0 to 24 h (AUC_0–24) on d 1 was comparable to that of IR tacrolimus on d 0, with a 90% confidence interval (CI) for MR/IR tacrolimus of 92%–97%. The AUC_0–24 value for MR tacrolimus on d 84 with the daily dose increased by 14% was approximately 17% lower than that for IR tacrolimus. The 90% CI was 77%–90%, outside the bioequivalence range of 80%–125%. There was a good correlation between AUC_0–24 and concentration at 24 h (C₂₄) for IR tacrolimus (d 0, r=0.930) and MR tacrolimus (d 1, r=0.936; d 84, r=0.903).

Conclusion:

The exposure to tacrolimus when administered MR tacrolimus once daily is not equivalent to that for IR tacrolimus twice daily after an 84-day conversion in Chinese stable liver transplant recipients. The dose should be adjusted on the basis of trough levels. The therapeutic drug monitoring for patients treated with IR tacrolimus is considered to be applicable to MR tacrolimus.     

A population pharmacokinetic study of tacrolimus in healthy Chinese volunteers and liver transplant patients

Aim:

To develop a population pharmacokinetic (PopPK) model of tacrolimus in healthy Chinese volunteers and liver transplant recipients for investigating the difference between the populations, and for potential individualized medication.

Methods:

A set of 1100 sparse trough concentration data points from 112 orthotopic liver transplant recipients, as well as 851 dense data points from 40 healthy volunteers receiving a single dose of tacrolimus (2 mg, po) were collected. PopPK model of tacrolimus was constructed using the program NONMEM. Related covariates such as age, hepatic and renal functions that were potentially associated with tacrolimus disposition were evaluated. The final model was validated using bootstrapping and a visual predictive check.

Results:

A two-compartment model of tacrolimus could best describe the data from the two populations. The final model including two covariates, population (liver transplant recipients or volunteers) and serum ALT (alanine aminotransferase) level, was verified and adequately described the pharmacokinetic characteristics of tacrolimus. The estimates of V2/F, Q/F and V3/F were 22.7 L, 76.3 L/h and 916 L, respectively. The estimated CL/F in the volunteers and liver transplant recipients was 32.8 and 18.4 L/h, respectively. Serum ALT level was inversely related to CL/F, whereas age did not influence CL/F. Thus, the elderly (≥65 years) and adult (<65 years) groups in the liver transplant recipients showed no significant difference in the clearance of tacrolimus.

Conclusion:

Compared with using the sparse data only, the integrating modeling technique combining sparse data from the patients and dense data from the healthy volunteers improved the PopPK analysis of tacrolimus.     

Lack of tacrolimus circadian pharmacokinetics and CYP3A5 pharmacogenetics in the early and maintenance stages in Japanese renal transplant recipients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Circadian variations of tacrolimus pharmacokinetics are controversial.
• Also, the pharmacokinetics has time-dependent variability, such as a decrease in oral clearance and increase in the dose-adjusted AUC after transplantation.
• Although the CYP3A5 polymorphism is associated with tacrolimus pharmacokinetics, differences in the influence of this gene on the pharmacokinetics between the early and maintenance stages have not yet been clarified.

WHAT THIS STUDY ADDS

• Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage with our designated-time administration strategy.
• Based on previous results and our own findings, the interval between food consumption and tacrolimus administration might influence the interindividual and interinstitutional variability of tacrolimus chronopharmacokinetics.
• The CYP3A5 polymorphism may be associated with the time-dependent changes in tacrolimus oral clearance.

AIMS

We investigated whether tacrolimus pharmacokinetics shows circadian variation and the influence of the CYP3A5 A6986G polymorphism on the pharmacokinetics in both the early and maintenance stages after renal transplantation.

METHODS

Tacrolimus was administered twice daily at specified times (09.00 and 21.00 h) throughout the pre- and post-transplant period according to the trough-targeting strategy. Fifty recipients with stable graft function were studied on day 28 and beyond 1-year post transplantation. Whole blood samples were collected prior to and 1, 2, 3, 4, 6, 9 and 12 h after both the morning and evening doses during hospitalization.

RESULTS

Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage [AUC_0–12 197.1 (95% confidence interval 182.9, 212.3) in daytime vs. 203.6 ng h ml⁻¹ (189.8, 217.4) in the night-time at day 28, 102.0 (92.1, 111.9) vs. 107.7 (97.9, 117.5) at 1 year, respectively]. In CYP3A5 *1 allele carriers (CYP3A5 expressers), body weight-adjusted oral clearance was markedly decreased from the early stage to the maintenance stage [0.622 (0.534, 0.709) to 0.369 l h⁻¹ kg⁻¹ (0.314, 0425)] compared with a smaller decrease [0.368 (0.305, 0.430) to 0.305 (0.217, 0.393)] in CYP3A5 non-expressers; however, the CYP3A5 genetic variation did not influence tacrolimus chronopharmacokinetics.

CONCLUSION

Equivalent daytime and night-time tacrolimus pharmacokinetics were achieved during both the early and maintenance stages with our specified-time administration strategy. The CYP3A5 polymorphism may be associated with the time-dependent changes in the oral clearance of tacrolimus, suggesting that genotyping of this polymorphism is useful for determining the appropriate dose of tacrolimus in both the early and maintenance stages after renal transplantation.     

Effect of CYP2C19 polymorphism on nelfinavir to M8 biotransformation in HIV patients

Aims

To evaluate the effect of CYP2C19 polymorphism on nelfinavir and M8 pharmacokinetic variability in human immunodeficiency virus-infected patients and to study the link between pharmacokinetic exposure and short-term efficacy and toxicity.

Methods

Nelfinavir (n = 120) and M8 (n = 119) concentrations were measured in 34 protease inhibitor-naïve patients. Two weeks after initiating the treatment, blood samples were taken before, 1, 3 and 6 h after drug administration. Genotyping for CYP3A4, 3A5, 2C19 and MDR1 was performed. A population pharmacokinetic model was developed to describe nelfinavir-M8 concentration time-courses and to estimate interpatient variability. The influence of individual characteristics and genotypes were tested using a likelihood ratio test. Estimated mean (C_mean), maximal (C_max) and trough (C_trough) nelfinavir and M8 concentrations were correlated to short-term virological efficacy and tolerance using Spearman nonparametric correlation tests.

Results

A one-compartment model with first-order absorption, elimination and metabolism to M8 best described nelfinavir data. M8 was modelled by an additional compartment. Mean pharmacokinetic estimates and the corresponding intersubject variabilities were: absorption rate 0.17 h⁻¹ (99%), absorption lag time 0.82 h, apparent nelfinavir total clearance 52 l h⁻¹ (49%), apparent nelfinavir volume of distribution 191 l, M8 elimination rate constant 1.76 h⁻¹ and nelfinavir to M8 0.39 h⁻¹ (59%) in *1/*1 patients and 0.20 h⁻¹ in *1/*2 or *2/*2 patients for CYP2C19*2. Nelfinavir C_mean was positively correlated to glycaemia and triglyceride increases (P = 0.02 and P = 0.04, respectively).

Conclusions

The rate of metabolism of nelfinavir to M8 was reduced by 50% in patients with *1/*2 or *2/*2 genotype for CYP2C19 compared with those with *1/*1 genotype.

What is already known about this subject

• Nelfinavir is an HIV protease inhibitor, substrate of the transporter P-glycoprotein and metabolized via CYP2C19, CYP3A4 and CYP3A5 enzymes.
• Pharmacokinetic studies have shown wide interindividual variability of nelfinavir concentrations, some of this variability perhaps caused by variant drug metabolism or transporter genes.
• For CYP3A4*1B and CYP3A5*3 polymorphism, results from three studies are in agreement, showing no difference in nelfinavir concentrations between patients with these different genotypes.
• However, for MDR1 and CYP2C19 polymorphism, there have been contradictory studies, showing either no impact on nelfinavir concentration or modified concentrations which could influence virological response.

What this study adds

• Patients with an *1/*2 or *2/*2 genotype for CYP2C19 had a nelfinavir to M8 biotransformation divided by 2 compared with *1/*1 patients.
• No evidence of any influence of MDR1 polymorphism on nelfinavir absorption could be detected.

     

Effect of CYP2C19*2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians

AIMS

To investigate the impact of CYP2C19 mutations *2-*6 and *17 on acid-inhibition and pharmacokinetics of lansoprazole (L15), omeprazole (O10, O20) and pantoprazole (P40) in Caucasians.

METHODS

CYP2C19 genotyping for *2–*6 and *17 mutations was assessed in subjects who were H. pylori negative in two randomized crossover trials. The influence of CYP2C19 mutations on single and repeated administration of L15 and O10 (study A) and O20 and P40 (study B) was investigated. Pharmacokinetics and the cumulative percentage of time with intragastric pH above 4 (% > pH 4) were assessed on day 1 and 6.

RESULTS

For study A CYP2C19 genotyping found five *1/*1, four *1/*2, one *1/*17 and one *2/*17. For study B the results were six *1/*1, two *1/*2, six *1/*17, one *2/*2 and one *2/*17. For all PPIs AUC was highest in *2/*2 and lowest in *1/*17. On day 1, all PPIs significantly increased percentage >pH 4 compared with baseline. *1/*1 genotype showed no significant acid-inhibition after L15, O10 and O20. *1/*17 genotype showed no significant acid-inhibition after O20 and P40. *1/*2 genotype showed significant acid-inhibition after L15 and O10. On day 6, all four PPIs showed significantly increased acid-inhibition. *1/*1 and *1/*17 showed a significantly increased percentage > pH 4 after treatment with O20 and P40. However, in *1/*1 subjects percentage > pH 4 was not significantly increased after L15 and O10. *1/*2 genotype showed a significant acid-inhibitory effect after repeated dosing with L15 and O10.

CONCLUSIONS

Caucasian subjects with *1/*1 and *1/*17 genotype need stronger acid-suppression therapy, especially during the first days of treatment or with on-demand therapy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The influence of CYP2C19 on the kinetics and dynamics of omeprazole, lansoprazole and rabeprazole has been studied in Japanese subjects.
• It has been suggested that subjects with *1/*1 genotype might need stronger acid suppression than *1/*2 and *2/*2 subjects. This suggestion comes from data in Japanese subjects and has not been confirmed in Caucasians.
• Furthermore, a novel CYP2C19 mutation, *17, which mainly occurs in Caucasians has been discovered. This mutation has been associated with clinical failure, but its relevance for therapy with PPIs has not been studied yet.

WHAT THIS STUDY ADDS

• In this study, the influence of CYP2C19 on both the pharmacokinetics and dynamics in Caucasian subjects after single and repeated dosing has been investigated.
• This is the first study showing that Caucasian subjects with *1/*1 and *1/*17 mutations need stronger acid-inhibition. In this study three proton pump inhibitors (omeprazole, lansoprazole and pantoprazole, in different doses) were studied of which pantoprazole had not been studied before in this setting, not even in Japanese.

     

Population pharmacokinetic modelling of aripiprazole and its active metabolite,dehydroaripiprazole, in psychiatric patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Almost all reported studies have investigated the pharmacokinetics of aripiprazole in healthy volunteers.
• The pharmacokinetics of dehydroaripiprazole have not been identified in a combined model with aripiprazole.

WHAT THIS STUDY ADDS

• The data on aripiprazole and dehydroaripiprazole in psychiatric patients were modelled jointly using a population approach.
• The apparent clearance of aripiprazole in cytochrome P450 (CYP) 2D6 intermediate metabolizers (IM) was approximately 60% of that in CYP2D6 extensive metabolizers (EM) having two functional alleles, but the exposure to dehydroaripiprazole in CYP2D6 IM was similar to that in EM.

AIMS

The aims of this study were to develop a combined population pharmacokinetic model for both aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients and to identify to what extent the genetic polymorphisms of cytochrome P450 (CYP) enzymes contribute to the variability in pharmacokinetics (PK).

METHODS

A population pharmacokinetic analysis was performed using NONMEM software based on 141 plasma concentrations at steady state from 80 patients receiving multiple oral doses of aripiprazole (10–30 mg day¹).

RESULTS

A one-compartment model with first-order kinetics for aripiprazole and dehydroaripiprazole each was developed to describe simultaneously the concentration data. The absorption rate constant was fixed to 1.06 h¹. The typical value of apparent distribution volume of aripiprazole was estimated to be 192 l. Covariate analysis showed that CYP2D6 genetic polymorphisms significantly influenced the apparent clearance of aripiprazole (CL/F), reducing the interindividual variability on CL/F from 37.8% CV (coefficient of variation) to 30.5%. The CL/F in the CYP2D6 IMs was approximately 60% of that in CYP2D6 EMs having two functional alleles. Based on the CYP2D6 genotype, the metabolic ratios were calculated at 0.20–0.34. However, the plasma concentration : dose ratios of dehydroaripiprazole were not different across the CYP2D6 genotype.

CONCLUSIONS

This population pharmacokinetic model provided an adequate fit to the data for both aripiprazole and dehydroaripiprazole in psychiatric patients. The usefulness of CYP genotyping as an aid to select the starting dose should be further investigated.     

A published pharmacogenetic algorithm was poorly predictive of tacrolimus clearance in an independent cohort of renal transplant recipients

Aims

An algorithm based on the CYP3A5 genotype to predict tacrolimus clearance to inform the optimal initial dose was derived using data from the DeKAF study (Passey et al. Br J Clin Pharmacol 2011; 72: 948–57) but was not tested in an independent cohort of patients. Our aim was to test whether the DeKAF dosing algorithm could predict estimated tacrolimus clearance in renal transplant recipients at our centre.

Methods

Predicted tacrolimus clearance based on the DeKAF algorithm was compared with dose-normalized trough whole-blood concentrations (estimated clearance) on day 7 after transplantation in a single-centre cohort of 255 renal transplant recipients.

Results

There was a weak correlation (r = 0.431) between clearance based on dose-normalized trough whole-blood concentrations and DeKAF algorithm-predicted clearance. The means of the tacrolimus clearance predicted by the DeKAF algorithm and the estimated tacrolimus clearance based on the dose-normalized trough blood concentrations were plotted against the differences in the clearance as a Bland–Altman plot. Logarithmic transformation was performed owing to the increased difference in tacrolimus clearance as the mean clearance increased. There was a highly significant systematic error (P < 0.0005) characterized by a sloped regression line [gradient, 0.88 (95% confidence interval, 0.75–1.01)] on the Bland–Altman plot.

Conclusions

The DeKAF algorithm was unable to predict the estimated tacrolimus clearance accurately based on real tacrolimus doses and blood concentrations in our cohort of patients. Other genes are known to influence the clearance of tacrolimus, and a polygenic algorithm may be more predictive than those based on a single genotype.     

Lopinavir/ritonavir population pharmacokinetics in neonates and infants

AIMS

Because of immature hepatic metabolism, lopinavir could present specific pharmacokinetics in the first weeks of life. We aimed at determining the optimal dosing regimen in neonates and infants weighing 1 to 10.5 kg.

METHODS

Lopinavir/ritonavir (LPV/r) pharmacokinetics were studied in 96 infants using a population approach.

RESULTS

A one-compartment model described LPV/r pharmacokinetics. Normalized to a 70 kg adult using allometry, clearance (CL/F) and distribution volume (V/F) estimates were 5.87 l h⁻¹ 70 kg⁻¹ and 91.7 l 70 kg⁻¹. The relative bioavailabilty, F, increased with post-menstrual age (PMA) and reached 50% of the adult value at 39.7 weeks.

CONCLUSIONS

Size and PMA explained some CL/F and V/F variability in neonates/infants. Based upon trough concentration limitations, suggested LPV/r dosing regimens were 40 mg 12 h⁻¹, 80 mg 12 h⁻¹ and 120 mg 12 h⁻¹ in the 1–2 kg, 2–6 kg and 6–10 kg group, respectively.     

Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation response to fluindione

AIM

Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients'' responses to coumarin derivatives. The role of these variants in fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to fluindione.

METHODS

Four hundred sixty-five patients with a venous thromboembolic event treated by fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, fluindione doses and bleeding events were collected.

RESULTS

VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001) and on the time to obtain a first INR value > 4 (P = 0.0002). The average daily dose of fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to fluindione.

CONCLUSIONS

VKORC1 genotype strongly affected anticoagulation induced by fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining.     

The pharmacokinetics of oxypurinol in people with gout

AIMS

Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations.

METHODS

Non-linear mixed effects modelling was applied to concentration–time data from 155 gouty patients with demographic, medical history and renal transporter genotype information.

RESULTS

A one compartment pharmacokinetic model with first order absorption best described the oxypurinol concentration–time data. Renal function and concomitant medicines (diuretics and probenecid), but not transporter genotype, significantly influenced oxypurinol pharmacokinetics and reduced the between subject variability in the apparent clearance of oxypurinol (CL/F_m) from 65% to 29%. CL/F_m for patients with normal, mild, moderate and severe renal impairment was 1.8, 0.6, 0.3 and 0.18 l h⁻¹, respectively. Model predictions showed a relationship between plasma oxypurinol and urate concentrations and failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines.

CONCLUSIONS

In conclusion, this first established pharmacokinetic model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degrees of renal impairment.     

Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects

AIMS

To evaluate the effect of co-administration of rifampicin, an inducer of cytochrome P450 (CYP)3A4, on the pharmacokinetics of roflumilast and roflumilast N-oxide. Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor, being developed for the treatment of chronic obstructive pulmonary disease. Roflumilast is metabolized by CYP3A4 and CYP1A2, with further involvement of CYP2C19 and extrahepatic CYP1A1. In vivo, roflumilast N-oxide contributes >90% to the total PDE4 inhibitory activity.

METHODS

Sixteen healthy male subjects were enrolled in an open-label, three-period, fixed-sequence study. They received a single oral dose of roflumilast 500 µg on days 1 and 12 and repeated oral doses of rifampicin 600 mg once daily on days 5–15. Plasma concentrations of roflumilast and roflumilast N-oxide were measured for up to 96 h. Test/Reference ratios and 90% confidence intervals (CIs) of geometric means for AUC and C_max of roflumilast and roflumilast N-oxide and for oral apparent clearance (CL/F) of roflumilast were estimated.

RESULTS

During the steady-state of rifampicin, the AUC_0–∞ of roflumilast decreased by 80% (point estimate 0.21; 90% CI 0.16, 0.27); C_max by 68% (0.32; CI 0.26, 0.39); for roflumilast N-oxide, the AUC_0–∞ decreased by 56% (0.44; CI 0.36, 0.55); C_max increased by 30% (1.30; 1.15, 1.48); total PDE4 inhibitory activity decreased by 58% (0.42; 0.38, 0.48).

CONCLUSIONS

Co-administration of rifampicin and roflumilast led to a reduction in total PDE4 inhibitory activity of roflumilast by about 58%. The use of potent cytochrome P450 inducers may reduce the therapeutic effect of roflumilast.