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Sökning: WFRF:(Roshammar Daniel)

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  • 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.
  • 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.
  • 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.
  • Röshammar, Daniel, et al. (författare)
  • Non-linear mixed effects modeling of antiretroviral drug response after administration of lopinavir, atazanavir and efavirenz containing regimens to treatment-naïve HIV-1 infected patients.
  • 2011
  • Ingår i: Journal of pharmacokinetics and pharmacodynamics. - 1573-8744. ; 38:6, s. 727-42
  • Tidskriftsartikel (refereegranskat)abstract
    • The objective of this analysis was to compare three methods of handling HIV-RNA data below the limit of quantification (LOQ) when describing the time-course of antiretroviral drug response using a drug-disease model. Treatment naïve Scandinavian HIV-positive patients (n = 242) were randomized to one of three study arms. Two nucleoside reverse transcriptase inhibitors were administrated in combination with 400/100 mg lopinavir/ritonavir twice daily, 300/100 mg atazanavir/ritonavir once a day or 600 mg efavirenz once a day. The viral response was monitored at screening, baseline and at 1, 2, 3, 4, 12, 24, 48, 96, 120, and 144 weeks after study initiation. Data up to 400 days was fitted using a viral dynamics non-linear mixed effects drug-disease model in NONMEM. HIV-RNA data below LOQ of 50 copies/ml plasma (39%) was omitted, replaced by LOQ/2 or included in the analysis using a likelihood-based method (M3 method). Including data below LOQ using the M3 method substantially improved the model fit. The drug response parameter expressing the fractional inhibition of viral replication was on average (95% CI) estimated to 0.787 (0.721-0.864) for lopinavir and atazanavir treatment arms and 0.868 (0.796-0.923) for the efavirenz containing regimen. At 400 days after treatment initiation 90% (76-100) of the lopinavir and atazanavir treated patients were predicted to have undetectable viral levels and 96% (89-100%) for the efavirenz containing treatment. Including viral data below the LOQ rather than omitting or replacing data provides advantages such as better model predictions and less biased parameter estimates which are of importance when quantifying antiretroviral drug response.
  • Aoki, Yasunori, 1982-, et al. (författare)
  • Model selection and averaging of nonlinear mixed-effect models for robust phase III dose selection
  • 2017
  • Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - 1567-567X .- 1573-8744. ; 44:6, s. 581-597
  • Tidskriftsartikel (refereegranskat)abstract
    • Population model-based (pharmacometric) approaches are widely used for the analyses of phase IIb clinical trial data to increase the accuracy of the dose selection for phase III clinical trials. On the other hand, if the analysis is based on one selected model, model selection bias can potentially spoil the accuracy of the dose selection process. In this paper, four methods that assume a number of pre-defined model structure candidates, for example a set of dose-response shape functions, and then combine or select those candidate models are introduced. The key hypothesis is that by combining both model structure uncertainty and model parameter uncertainty using these methodologies, we can make a more robust model based dose selection decision at the end of a phase IIb clinical trial. These methods are investigated using realistic simulation studies based on the study protocol of an actual phase IIb trial for an oral asthma drug candidate (AZD1981). Based on the simulation study, it is demonstrated that a bootstrap model selection method properly avoids model selection bias and in most cases increases the accuracy of the end of phase IIb decision. Thus, we recommend using this bootstrap model selection method when conducting population model-based decision-making at the end of phase IIb clinical trials.
  • 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.
  • Mukonzo, Jackson K, et al. (författare)
  • HIV/AIDS Patients Display Lower Relative Bioavailability of Efavirenz than Healthy Subjects.
  • 2011
  • Ingår i: Clinical pharmacokinetics. - 0312-5963. ; 50:8, s. 531-40
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Pharmacokinetic studies of antiretroviral drugs are often conducted in adult healthy subjects, and the results are extrapolated to HIV/AIDS patients. HIV/AIDS, however, is known to cause morphological and physiological changes that may alter the pharmacokinetics of antiretroviral drugs. We examined the effect of HIV/AIDS on the pharmacokinetics of efavirenz in Ugandans. Methods: After a first oral dose of efavirenz 600 mg in treatment-naïve HIV-infected patients, blood samples were collected at nine time points up to 24 hours. The plasma-concentration time data from these patients were merged with previously reported data from adult healthy subjects. Population pharmacokinetic models were fitted to the data, using NONMEM VI software. Covariate analyses were performed to estimate the effects of HIV/AIDS disease, demographic characteristics (sex, bodyweight, age), biochemical variables (serum creatinine, urea, alanine aminotransferase) and pharmacogenetic variation in cytochrome P450 (CYP) 2B6, CYP3A5 and adenosine triphosphate-binding cassette, sub-family B, member 1 (ABCB1) on the population pharmacokinetic parameters. Results: Efavirenz plasma concentration-time data obtained from 29 HIV-1-infected, treatment-naïve patients were merged with previously reported data from 32 adult healthy subjects. The model identified sex and HIV/AIDS disease as statistically significant categorical predictors of efavirenz pharmacokinetics. Females were predicted to have a 2-fold higher volume of distribution of the peripheral compartment after oral administration (V(2)/F) than males (95% CI 1.53, 2.63), while HIV/AIDS patients were found to have 30% lower relative bioavailability (95% CI 18.7, 40.7) than healthy subjects. The increased V(2)/F in females resulted in a 2-fold longer elimination half-life than in males. Conclusion: On the basis of the findings of this analysis, we conclude that, apart from bodyweight-based differences, both HIV/AIDS disease and sex affect efavirenz pharmacokinetics in Ugandans. HIV/AIDS disease is associated with reduced relative bioavailability of efavirenz. We recommend that findings from healthy subject studies be confirmed in HIV/AIDS patients and that caution be applied in direct extrapolation of exposure data to the target patient population.
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