1.
Ahn, Jae Eun, et al.
(författare)
Likelihood based approaches to handling data below the quantification limit using NONMEM VI
2008
Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 35:4, s. 401-421
Tidskriftsartikel (refereegranskat) abstract
PURPOSE: To evaluate the likelihood-based methods for handling data below the quantification limit (BQL) using new features in NONMEM VI. METHODS: A two-compartment pharmacokinetic model with first-order absorption was chosen for investigation. Methods evaluated were: discarding BQL observations (M1), discarding BQL observations but adjusting the likelihood for the remaining data (M2), maximizing the likelihood for the data above the limit of quantification (LOQ) and treating BQL data as censored (M3), and like M3 but conditioning on the observation being greater than zero (M4). These four methods were compared using data simulated with a proportional error model. M2, M3, and M4 were also compared using data simulated from a positively truncated normal distribution. Successful terminations and bias and precision of parameter estimates were assessed. RESULTS: For the data simulated with a proportional error model, the overall performance was best for M3 followed by M2 and M1. M3 and M4 resulted in similar estimates in analyses without log transformation. For data simulated with the truncated normal distribution, M4 performed better than M3. CONCLUSIONS: Analyses that maximized the likelihood of the data above the LOQ and treated BQL data as censored provided the most accurate and precise parameter estimates.
2.
Dansirikul, Chantaratsamon, et al.
(författare)
Approaches to handling pharmacodynamic baseline responses
2008
Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 35:3, s. 269-283
Tidskriftsartikel (refereegranskat) abstract
A few approaches for handling baseline responses are available for use in pharmacokinetic (PK)-pharmacodynamic (PD) analysis. They include: (method 1-B1) estimation of the typical value and interindividual variability (IIV) of baseline in the population, (B2) inclusion of the observed baseline response as a covariate acknowledging the residual variability, (B3) a more general version of B2 as it also takes the IIV of the baseline in the population into account, and (B4) normalization of all observations by the baseline value. The aim of this study was to investigate the relative performance of B1-B4. PD responses over a single dosing interval were simulated from an indirect response model in which a drug acts through stimulation or inhibition of the response according to an Emax model. The performance of B1-B4 was investigated under 22 designs, each containing 100 datasets. NONMEM VI beta was used to estimate model parameters with the FO and the FOCE method. The mean error (ME, %) and root mean squared error (RMSE, %) of the population parameter estimates were computed and used as an indicator of bias and imprecision. Absolute ME (|ME|) and RMSE from all methods were ranked within the same design, the lower the rank value the better method performance. Average rank of each method from all designs was reported. The results showed that with B1 and FOCE, the average of |ME| and RMSE across all typical individual parameters and all conditions was 5.9 and 31.8%. The average rank of |ME| for B1, B2, B3, and B4 was 3.7, 3.8, 3.3, and 5.2 for the FOCE method, and 4.6, 4.3, 4.7, and 6.4 for the FO method. The smallest imprecision was noted with the use of B1 (rank of 3.1 for FO, and 2.9 for FOCE) and increased, in order, with B3 (3.9-FO and 3.6-FOCE), B2 (4.8-FO; 4.7-FOCE), and B4 (6.4-FO; 6.5-FOCE). We conclude that when considering both bias and imprecision B1 was slightly better than B3 which in turn was better than B2. Differences between these methods were small. B4 was clearly inferior. The FOCE method led to a smaller bias, but no marked reduction in imprecision of parameter estimates compared to the FO method.
3.
Elsherbiny, Doaa A, et al.
(författare)
A model based assessment of the CYP2B6 and CYP2C19 inductive properties by artemisinin antimalarials: implications for combination regimens.
2008
Ingår i: Journal of pharmacokinetics and pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 35:2, s. 203-17
Tidskriftsartikel (refereegranskat) abstract
The study aim was to assess the inductive properties of artemisinin antimalarials using mephenytoin as a probe for CYP2B6 and CYP2C19 enzymatic activity. The population pharmacokinetics of S-mephenytoin and its metabolites S-nirvanol and S-4'-hydroxymephenytoin, including enzyme turn-over models for induction, were described by nonlinear mixed effects modeling. Rich data (8-16 samples/occasion/subject) were collected from 14 healthy volunteers who received mephenytoin before and during ten days of artemisinin administration. Sparse data (3 samples/occasion/subject) were collected from 74 healthy volunteers who received mephenytoin before, during and after five days administration of artemisinin, dihydroartemisinin, arteether, artemether or artesunate. The production rate of CYP2B6 was increased 79.7% by artemisinin, 61.5% by arteether, 76.1% by artemether, 19.9% by dihydroartemisinin and 16.9% by artesunate. The production rate of CYP2C19 increased 51.2% by artemisinin, 14.8% by arteether and 24.9% by artemether. In conclusion, all studied artemisinin derivatives induced CYP2B6. CYP2C19 induction by arteether and artemether as well as CYP2B6 and CYP2C19 induction by artemisinin was confirmed. The inductive capacity is different among the artemisinin drugs, which is of importance when selecting drugs to be used in antimalarial combination therapy such that the potential for drug-drug interactions is minimized.
4.
Fanta, Samuel, et al.
(författare)
Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of ABCB1 polymorphisms
2008
Ingår i: Pharmacogenetics and genomics. - 1744-6872. ; 18:2, s. 77-90
Tidskriftsartikel (refereegranskat) abstract
OBJECTIVE: To evaluate whether variations in the ABCB1, ABCC2, SLCO1B1, CYP3A4, CYP3A5, or NR1I2 genes are associated with the pharmacokinetics of cyclosporine in pediatric renal transplant candidates, and whether the effects of these variants are related to age. METHODS: A total of 104 pediatric patients (aged 0.36-16.3 years) were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. The patients had undergone a pharmacokinetic study with intravenous and oral ciclosporine (INN, cyclosporin) before renal transplantation. RESULTS: In the whole population, the mean+/-SD cyclosporine oral bioavailability was 0.38+/-0.09, volume of distribution was 2.3+/-0.54 l/kg, and systemic clearance normalized by allometric body weight was 0.88+/-0.16 l/h/kg3/4. The prehepatic extraction ratio was 0.51+/-0.13, and the hepatic extraction ratio was 0.24+/-0.04, the former explaining 95% of the variability in oral bioavailability (P<0.0001). In children older than 8 years, the pre-hepatic extraction was 0.64+/-0.09 in those with the ABCB1 c.2677GG genotype, 0.52+/-0.11 in those with the c.2677GT genotype, and 0.41+/-0.03 in those with the c.2677TT genotype (P=0.021, r2=0.334), leading to corresponding differences in oral bioavailability (0.28+/-0.07, 0.36+/-0.07, and 0.44+/-0.04, respectively; P=0.012, r2=0.372). Similar associations were observed with the ABCB1 c.1236C>T variant and the related haplotype c.1199G-c.1236C-c.2677G-c.3435C (P<0.05). The estimated oral dose requirement and clearance of cyclosporine remained largely unexplained by the genetic variations. CONCLUSIONS: Although these data suggest an age-related effect of ABCB1 polymorphism on oral bioavailability, further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.
5.
Hooker, Andrew C, et al.
(författare)
Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function : incorporating cytochrome P4503A activity measurements
2008
Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 84:1, s. 111-118
Tidskriftsartikel (refereegranskat) abstract
The relationship between cytochrome P4503A4 (CYP3A4) activity and docetaxel clearance in patients with varying degrees of liver function (LF) was evaluated. Docetaxel 40, 50, or 75 mg/m(2) was administered to 85 patients with advanced cancer; 23 of 77 evaluable patients had abnormalities in LF tests. Baseline CYP3A activity was assessed using the erythromycin breath test (ERMBT). Pharmacokinetic studies and toxicity assessments were performed during cycle 1 of therapy and population modeling was performed using NONMEM. Docetaxel unbound clearance was lower (317 vs. 470 l/h) and more variable in patients with LF abnormalities compared to patients with normal LF. Covariates evaluated accounted for 83% of variability on clearance in patients with liver dysfunction, with CYP3A4 activity accounting for 47% of variation; covariates accounted for only 23% of variability in patients with normal LF. The clinical utility of the ERMBT may lie in identifying safe docetaxel doses for patients with LF abnormalities.
6.
Kjellsson, Maria C., 1975-
(författare)
Methodological Studies on Models and Methods for Mixed-Effects Categorical Data Analysis
2008
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Effects of drugs are in clinical trials often measured on categorical scales. These measurements are increasingly being analyzed using mixed-effects logistic regression. However, the experience with such analyzes is limited and only a few models are used. The aim of this thesis was to investigate the performance and improve the use of models and methods for mixed-effects categorical data analysis. The Laplacian method was shown to produce biased parameter estimates if (i) the data variability is large or (ii) the distribution of the responses is skewed. Two solutions are suggested; the Gaussian quadrature method and the back-step method. Two assumptions made with the proportional odds model have also been investigated. The assumption with proportional odds for all categories was shown to be unsuitable for analysis of data arising from a ranking scale of effects with several underlying causes. An alternative model, the differential odds model, was developed and shown to be an improvement, in regard to statistical significance as well as predictive performance, over the proportional odds model for such data. The appropriateness of the likelihood ratio test was investigated for an analysis where dependence between observations is ignored, i.e. performing the analysis using the proportional odds model. The type I error was found to be affected; thus assessing the actual critical value is prudent in order to verify the statistical significance level. An alternative approach is to use a Markov model, in which dependence between observations is incorporated. In the case of polychotomous data such model may involve considerable complexity and thus, a strategy for the reduction of the time-consuming model building with the Markov model and sleep data is presented. This thesis will hopefully contribute to a more confident use of models for categorical data analysis within the area of pharmacokinetic and pharmacodynamic modelling in the future.
