Population Pharmacokinetics of Lopinavir/Ritonavir (Kaletra) in HIV-Infected Patients
| Autor: | Esteban Ribera Pascuet, Salvador Cabrera Figueroa, Dolores Santos Buelga, María José García Sánchez, Alfonso Domínguez-Gil Hurlé, Rosa María López Galera, Elena López Aspiroz |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Anti-HIV Agents Population Lopinavir/ritonavir HIV Infections Pharmacology Models Biological Lopinavir Pharmacokinetics medicine Humans Pharmacology (medical) education education.field_of_study Ritonavir business.industry Reproducibility of Results Middle Aged NONMEM Atazanavir Drug Combinations Female Drug Monitoring business Saquinavir medicine.drug |
| Zdroj: | Therapeutic Drug Monitoring. 33:573-582 |
| ISSN: | 0163-4356 |
| Popis: | Background A relationship between plasma concentrations and viral suppression in patients receiving lopinavir (LPV)/ritonavir (RTV) has been observed. Therefore, it is important to increase our knowledge about factors that determine interpatient variability in LPV pharmacokinetics (PK). Methods The study, designed to develop and validate population PK models for LPV and RTV, involved 263 ambulatory patients treated with 400/100 mg of LPV/RTV twice daily. A database of 1110 concentrations of LPV and RTV (647 from a single time-point and 463 from 73 full PK profiles) was available. Concentrations were determined at steady state using high-performance liquid chromatography with ultraviolet detection. PK analysis was performed with NONMEM software. Age, gender, height, total body weight, body mass index, RTV trough concentration (RTC), hepatitis C virus coinfection, total bilirubin, hospital of origin, formulation and concomitant administration of efavirenz (EFV), saquinavir (SQV), atazanavir (ATV), and tenofovir were analyzed as possible covariates influencing LPV/RTV kinetic behavior. Results Population models were developed with 954 drug plasma concentrations from 201 patients, and the validation was conducted in the remaining 62 patients (156 concentrations). A 1-compartment model with first-order absorption (including lag-time) and elimination best described the PK. Proportional error models for interindividual and residual variability were used. The final models for the drugs oral clearance (CL/F) were as follows: CL/F(LPV)(L/h)=0.216·BMI·0.81(RTC)·1.25(EFV)·0.84(ATV); CL/F(RTV)(L/h) = 8.00·1.34(SQV)·1.77(EFV)·1.35(ATV). The predictive performance of the final population PK models was tested using standardized mean prediction errors, showing values of 0.03 ± 0.74 and 0.05 ± 0.91 for LPV and RTV, and normalized prediction distribution error, confirming the suitability of both models. Conclusions These validated models could be implemented in clinical PK software and applied to dose individualization using a Bayesian approach for both drugs. |
| Databáze: | OpenAIRE |
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