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Sökning: WFRF:(Röshammar Daniel 1979 )

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1.
  • Mukonzo, K, et al. (författare)
  • A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans.
  • 2009
  • Ingår i: British journal of clinical pharmacology. - 1365-2125. ; 68:5, s. 690-9
  • Tidskriftsartikel (refereegranskat)abstract
    • center dot Efavirenz is metabolized by highly polymorphic enzymes, CYP2B6 and CYP3A. The effect of the different variant alleles on efavirenz population pharmacokinetics has not yet been fully explored. center dot CYP2B6*6 influences efavirenz steady-state pharmacokinetics. Together with sex it explains 11% of the between-subject variability in apparent oral clearance, but predictions could potentially be improved if additional alleles causing reduced drug metabolism were identified. center dot ABCB1 (3435C -> T) may have effect on efavirenz single-dose and steady-state pharmacokinetics. WHAT THIS STUDY ADDS center dot A new polymorphism in ABCB1 gene (rs3842) and CYP2B6*11 in addition to sex and CYP2B6*6 genotype predict efavirenz single-dose pharmacokinetics. center dot A combined population pharmacogenetic/pharmacokinetic modelling approach allows determination and simulation of determinant factors for efavirenz single-dose pharmacokinetics based on data on gender, biochemical variables and genetic factors in relevant genes (a total of 30 SNPs in CYP2B6, ABCB1 and CYP3A4 genes) in Ugandan population. AIMS Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using nonmem. METHODS Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero- followed by first-order absorption. RESULTS Apparent oral clearance (95% confidence interval) was 4 l h l-1 (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONS The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.
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2.
  • Rekic, Dinko, et al. (författare)
  • Bilirubin-a potential marker of drug exposure in atazanavir-based antiretroviral therapy.
  • 2011
  • Ingår i: The AAPS journal. - 1550-7416. ; 13:4, s. 598-605
  • Tidskriftsartikel (refereegranskat)abstract
    • The objective of this work was to examine the atazanavir-bilirubin relationship using a population-based approach and to assess the possible application of bilirubin as a readily available marker of atazanavir exposure. A model of atazanavir exposure and its concentration-dependent effect on bilirubin levels was developed based on 200 atazanavir and 361 bilirubin samples from 82 patients receiving atazanavir in the NORTHIV trial. The pharmacokinetics was adequately described by a one-compartment model with first-order absorption and lag-time. The maximum inhibition of bilirubin elimination rate constant (I (max)) was estimated at 91% (95% CI, 87-94) and the atazanavir concentration resulting in half of I (max) (IC50) was 0.30 mu mol/L (95% CI, 0.24-0.37). At an atazanavir/ritonavir dose of 300/100 mg given once daily, the bilirubin half-life was on average increased from 1.6 to 8.1 h. A nomogram, which can be used to indicate suboptimal atazanavir exposure and non-adherence, was constructed based on model simulations.
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3.
  • Rekic, Dinko, et al. (författare)
  • Model based design and analysis of phase II HIV-1 trials
  • 2013
  • Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - 1567-567X .- 1573-8744. ; 40:4, s. 487-496
  • Tidskriftsartikel (refereegranskat)abstract
    • This work explores the advantages of a model based drug development (MBDD) approach for the design and analysis of antiretroviral phase II trials. Two different study settings were investigated: (1) a 5-arm placebo-controlled parallel group dose-finding/proof of concept (POC) study and (2) a comparison of investigational drug and competitor. Studies were simulated using a HIV-1 dynamics model in NONMEM. The Monte-Carlo Mapped Power method determined the sample size required for detecting a dose-response relationship and a significant difference in effect compared to the competitor using a MBDD approach. Stochastic simulation and re-estimation were used for evaluation of model parameter precision and bias given different sample sizes. Results were compared to those from an unpaired, two-sided t test and ANOVA (p a parts per thousand currency sign 0.05). In all scenarios, the MBDD approach resulted in smaller study sizes and more precisely estimated treatment effect than conventional statistical analysis. Using a MBDD approach, a sample size of 15 patients could be used to show POC and estimate ED50 with a good precision (relative standard error, 25.7 %). A sample size of 10 patients per arm was needed using the MBDD approach for detecting a difference in treatment effect of a parts per thousand yen20 % at 80 % power, a 3.4-fold reduction in sample size compared to a t test. The MBDD approach can be used to achieve more precise dose-response characterization facilitating decision making and dose selection. If necessitated, the sample size needed to reach a desired power can potentially be reduced compared to traditional statistical analyses. This may allow for comparison against competitors already in early clinical studies.
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4.
  • Friberg Hietala, Sofia, 1973-, et al. (författare)
  • Population pharmacokinetics of amodiaquine and desethylamodiaquine in pediatric patients with uncomplicated falciparum malaria
  • 2007
  • Ingår i: JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS. - 1567-567X. ; 34:5, s. 669-686
  • Tidskriftsartikel (refereegranskat)abstract
    • The study aimed to characterize the population pharmacokinetics of amodiaquine (AQ) and its major metabolite N-desethylamodiaquine (N-DEAQ), and to assess the correlation between exposure to N-DEAQ and treatment outcome. Blood samples from children in two studies in Zanzibar and one in Papua New Guinea were included in the pharmacokinetic analysis (n = 86). The children had been treated with AQ in combination with artesunate or sulphadoxine-pyrimethamine. The population pharmacokinetics of AQ and N-DEAQ were modeled using the non-linear mixed effects approach as implemented in NONMEM. Bayesian post-hoc estimates of individual pharmacokinetic parameters were used to generate individual profiles of N-DEAQ exposure. The correlation between N-DEAQ exposure and effect was studied in 212 patients and modeled with logistic regression in NONMEM. The pharmacokinetics of AQ and N-DEAQ were best described by two parallel two-compartment models with a central and a peripheral compartment for each compound. The systemic exposure to AQ was low in comparison to N-DEAQ. The t (1/2lambda) of N-DEAQ ranged from 3 days to 12 days. There was a statistically significant, yet weak, association between N-DEAQ concentration on day 7 and treatment outcome. The age-based dosing schedule currently recommended in Zanzibar appeared to result in inadequate exposure to N-DEAQ in many patients.
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5.
  • Nyakutira, C, et al. (författare)
  • High prevalence of the CYP2B6 516G-->T(*6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe.
  • 2007
  • Ingår i: European Journal of Clinical Pharmacology. - 0031-6970. ; 64:4, s. 357-365
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: The study sought to investigate the relationship between efavirenz exposure and the CYP2B6 516G-->T(*6) genotype in HIV/AIDS outpatients, using pharmacokinetic modelling and simulation. METHODS: Blood samples where obtained from 74 outpatients treated with a combination regimen including 600 mg efavirenz daily for a duration of at least 3 weeks at clinics in Harare, Zimbabwe. The subjects were genotyped for the major CYP2B6 variant, CYP2B6*6, associated with reduced enzyme activity, using a PCR-RFLP method. Efavirenz plasma concentrations were determined by HPLC-UV. Population pharmacokinetic modelling and simulation of the data were performed in NONMEM VI. RESULTS: A high allele frequency of the CYP2B6*6 allele of 49% was observed. Efavirenz plasma concentrations were above 4 mg/L in 50% of the patients. Genotype and sex were identified as predictive covariates of efavirenz disposition. Pharmacokinetic parameter estimates indicate that a dose reduction to 400 mg efavirenz per day is possible in patients homozygous for the CYP2B6*6 genotype without compromising therapeutic efficacy. CONCLUSION: The CYP2B6*6 allele occurs at a high frequency in people of African origin and is associated with high efavirenz concentrations. Simulations indicate that an a priori 35% dose reduction in homozygous CYP2B6*6 patients would maintain drug exposure within the therapeutic range in this group of patients. Our preliminary results suggest the conduct of a prospective clinical dose optimization study to evaluate the utility of genotype-driven dose adjustment in this population.
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6.
  • Rekić, Dinko, 1984-, et al. (författare)
  • In silico prediction of efavirenz and rifampicin drug-drug interaction considering weight and CYP2B6 phenotype
  • 2011
  • Ingår i: British Journal of Clinical Pharmacology. - 0306-5251. ; 71:4, s. 536-43
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: To test whether a pharmacokinetic simulation model could extrapolate non-clinical drug data to predict human efavirenz exposure after single and continuous dosing as well as the effects of concomitant rifampicin and further to evaluate the weight based dosage recommendations used to counteract the rifampicin-efavirenz interaction. Methods: Efavirenz pharmacokinetics were simulated using a physiologically-based pharmacokinetic model implemented in the Simcyp population-based simulator. Physicochemical and metabolism data obtained from the literature were used as input for prediction of pharmacokinetic parameters. The model was used to simulate the effects of rifampicin on efavirenz pharmacokinetics in 400 virtual patients, taking into account bodyweight and CYP2B6 phenotype. Results: Apart from the absorption phase, the simulation model predicted efavirenz concentration-time profiles reasonably well with close agreement with clinical data. The simulated effects of rifampicin co-administration on efavirenz treatment showed only a minor decrease of 16% (95%CI 13; 19) in efavirenz area under the concentration-time curve (AUC), in magnitude with what has been clinically observed (22%). Efavirenz exposure depended on CYP2B6 phenotype and bodyweight. Increasing the efavirenz dose during concomitant rifampicin was predicted to be most successful in patients over 50 kg regardless of CYP2B6 status. Conclusion: Our findings, although based on a simulation approach using limited in vitro data, support the current recommendations for using a 50 kg bodyweight cut-off for efavirenz dose increment when co-treating with rifampicin.
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7.
  • Röshammar, Daniel, 1979- (författare)
  • Applied Population Pharmacokinetic/ Pharmacodynamic Modeling of Antiretroviral and Antimalarial Drug Therapy
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • HIV/AIDS and malaria are two major global infectious diseases. Although better drugs against these conditions are becoming more available, dosages may not always be optimal with respect to effectiveness, safety, cost or convenience of administration. This thesis aims to quantitate the pharmacological relationship between dosing history, sources of variation between individuals, drug exposure and response to selected antiretroviral and antimalarial regimens. Pharmacometric, i.e. pharmaco-statistical, models were fitted to observed data from five clinical studies, using the nonmem software. Several polymorphic genes coding for drug metabolizing enzymes and transporters were found to have impact on the disposition of the non-nucleoside reverse transcriptase inhibitor efavirenz in healthy Ugandan subjects after single dose administration. Moreover, using simulation it was demonstrated that a 200 mg dose reduction in Zimbabwean HIV-patients with genetically decreased metabolic capacity would maintain efavirenz exposure within the therapeutic range during repeated administration. In a typical clinical trial large amounts of drug response data are collected. However, usually only limited amounts of the recorded data are actually used for investigating differences between regimens. Herein, a drug-disease model was developed to describe the time-course of repeatedly measured HIV-RNA levels in Scandinavian patients randomized to one of three commonly prescribed antiretroviral regimens. The initial analysis showed that an efavirenz-containing regimen appeared to be more efficacious compared to two protease inhibitor-containing regimens. Antimalarial artemisinin-based combination therapy bears many resemblances to antiretroviral treatment. The drugs exhibit variable and complex pharmacokinetics and the diseases themselves bring reasonable possibilities for pharmacodynamic assessment. Auto-induction of drug metabolism was described after multiple dosing with artemisinin in Vietnamese patients. The frequency of recrudescent malaria infection was as high as 37% but could not directly be linked to low artemisinin exposure. The elimination half-life of piperaquine, a suitable partner drug for artemisinin-based combination treatment, was estimated to 12 days with large between-subject variability. The thesis demonstrates the utility of pharmacometric methodology in the analysis of clinical data originating from high-income countries as well as resource-limited settings. Ultimately it can be a tool for decision analysis and policy making.
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8.
  • Röshammar, Daniel, 1979-, et al. (författare)
  • Pharmacokinetics of piperaquine after repeated oral administration of the antimalarial combination CV8 in 12 healthy male subjects
  • 2006
  • Ingår i: Eur J Clin Pharmacol. ; 62:5, s. 335-41
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To investigate the pharmacokinetic properties of piperaquine after repeated oral administration of the antimalarial combination CV8 in healthy subjects. METHODS: Twelve healthy fasted Vietnamese males were administered four tablets CV8 (320 mg piperaquine phosphate, 32 mg dihydroartemisinin, 5 mg primaquine phosphate, 90 mg trimethoprim) on day 1, followed by two tablets every 24th hour, for a total of 3 days. Blood samples were frequently drawn on days 1 and 3 and sparsely drawn until day 29. Samples were analyzed for piperaquine using solid phase extraction followed by high-performance liquid chromatography. Population pharmacokinetic parameter estimates were obtained by nonlinear mixed effects modeling of the observed data using NONMEM. RESULTS: A two-compartment disposition model with an absorption lag time described the observed piperaquine concentrations. Absorption profiles were found to be irregular with double or multiple peaks. A dual pathway first-order absorption model improved the goodness of fit. Piperaquine pharmacokinetics were characterized by a large volume of distribution and a terminal half-life of several days. Estimates [95% confidence interval (CI)] of CL/F, V(ss)/F and t(1/2)(z) were found to be 56.4 (29-84) l/h, 6,000 (3,500-8,500) l and 11.7 (8.3-15.7) days, respectively. CONCLUSION: Piperaquine pharmacokinetics after repeated oral doses were characterized by multiple concentration peaks and multiphasic disposition, resulting in a long terminal half-life. Sustained exposure to the drug after treatment should be taken into account when designing future clinical studies, e.g. duration of follow-up, and may also drive resistance development in areas of high malaria transmission.
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