Population pharmacokinetics of lopinavir/ritonavir (Kaletra) in HIV-infected patients
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2011 |
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| Erschienen: |
2011 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:33 |
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| Enthalten in: |
Therapeutic drug monitoring - 33(2011), 5 vom: 01. Okt., Seite 573-82 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
López Aspiroz, Elena [VerfasserIn] |
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| Links: |
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| Themen: |
2494G1JF75 |
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| Anmerkungen: |
Date Completed 26.01.2012 Date Revised 21.11.2013 published: Print Citation Status MEDLINE |
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| doi: |
10.1097/FTD.0b013e31822d578b |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM211420484 |
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| 245 | 1 | 0 | |a Population pharmacokinetics of lopinavir/ritonavir (Kaletra) in HIV-infected patients |
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| 500 | |a Date Completed 26.01.2012 | ||
| 500 | |a Date Revised 21.11.2013 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSIONS: These validated models could be implemented in clinical PK software and applied to dose individualization using a Bayesian approach for both drugs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Anti-HIV Agents |2 NLM | |
| 650 | 7 | |a Drug Combinations |2 NLM | |
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| 650 | 7 | |a Lopinavir |2 NLM | |
| 650 | 7 | |a 2494G1JF75 |2 NLM | |
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| 700 | 1 | |a Domínguez-Gil Hurlé, Alfonso |e verfasserin |4 aut | |
| 700 | 1 | |a García Sánchez, María José |e verfasserin |4 aut | |
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