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1.  Pharmacokinetic Interaction between Nevirapine and Nortriptyline in Rats: Inhibition of Nevirapine Metabolism by Nortriptyline 
Antimicrobial Agents and Chemotherapy  2014;58(12):7041-7048.
One of the most frequent comorbidities of HIV infection is depression, with a lifetime prevalence of 22 to 45%. Therefore, it was decided to study a potential pharmacokinetic interaction between the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) and the tricyclic antidepressant nortriptyline (NT). NVP and NT were administered to rats either orally, intraduodenally, or intravenously, and the changes in plasma levels and pharmacokinetic parameters were analyzed. Experiments with rat and human hepatic microsomes were carried out to evaluate the inhibitory effects of NT on NVP metabolism. NVP plasma concentrations were significantly higher when this drug was coadministered with NT. The maximum plasma concentrations of NVP were increased 2 to 5 times and the total plasma clearance was decreased 7-fold in the presence of NT. However, statistically significant differences in the pharmacokinetic parameters of NT in the absence and presence of NVP were not found. In vitro studies with rat and human hepatic microsomes confirmed the inhibition of NVP hepatic metabolism by NT in a concentration-dependent way, with the inhibition being more intense in the case of rat microsomes. In conclusion, a pharmacokinetic interaction between NVP and NT was detected. This interaction was a consequence of the inhibition of hepatic metabolism of NVP by NT. In vivo human studies are required to evaluate the effects of this interaction on the pharmacokinetics of NVP before it can be taken into account for patients receiving NVP.
PMCID: PMC4249572  PMID: 25224004
2.  Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability 
Human immunodeficiency virus (HIV) type-1 non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of acquired immune deficiency syndrome (AIDS)/HIV infection.
First-generation NNRTIs, nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV) are drugs with a low genetic barrier and poor resistance profile, which has led to the development of new generations of NNRTIs. Second-generation NNRTIs, etravirine (ETR) and rilpivirine (RPV) have been approved by the Food and Drug Administration and European Union, and the next generation of drugs is currently being clinically developed. This review describes recent clinical data, pharmacokinetics, metabolism, pharmacodynamics, safety and tolerability of commercialized NNRTIs, including the effects of sex, race and age differences on pharmacokinetics and safety. Moreover, it summarizes the characteristics of next-generation NNRTIs: lersivirine, GSK 2248761, RDEA806, BILR 355 BS, calanolide A, MK-4965, MK-1439 and MK-6186.
This review presents a wide description of NNRTIs, providing useful information for researchers interested in this field, both in clinical use and in research.
PMCID: PMC3764307  PMID: 24008177
human immunodeficiency virus; non-nucleoside reverse transcriptase inhibitors; nevirapine; delavirdine; efavirenz; etravirine; rilpivirine; next-generation non-nucleoside reverse transcriptase inhibitors
3.  Population pharmacokinetic analysis of vancomycin in neonates. A new proposal of initial dosage guideline 
To determine the population pharmacokinetic parameters of vancomycin in neonatal patients with a wide range of gestational age and birth weight, and subsequently to design an initial dosing schedule for vancomycin in neonates.
Using nonlinear mixed-effects modelling (NONMEM VI), the pharmacokinetics of vancomycin were investigated in 70 neonates with postmenstrual age and body weight ranging 25.1–48.1 weeks and 0.7–3.7 kg, respectively. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data. Nine demographic characteristics and 21 co-administered drugs were evaluated as covariates of clearance (CL) and distribution volume (Vd) of vancomycin.
Weight-normalized clearance of vancomycin was influenced by postmenstrual age (PMA) and co-administration of amoxicillin-clavulanic acid. Weight-normalized volume of distribution was influenced by co-administration of spironolactone. CL and Vd of the typical individual in this study population (PMA = 34.6 weeks, weight = 1.7 kg) were estimated to be 0.066 l h−1 kg−1 (95% CI 0.059, 0.073 l h−1 kg−1) and 0.572 l kg−1 (95% CI 0.505, 0.639 l kg−1), respectively. This model was used to predict a priori serum vancomycin concentrations in a validation group (n= 41), which were compared with observed concentrations to determine the predictive performance of the model. The 95% confidence interval of mean prediction error included zero for both peak and trough vancomycin concentrations.
Postmenstrual age, co-administration of amoxicillin-clavulanic acid and spironolactone have a significant effect on the weight-normalized CL and Vd. An initial dosage guideline for vancomycin is proposed for preterm and full-term neonates, whereas the population pharmacokinetic model can be used for dosage individualization of vancomycin.
PMCID: PMC2997311  PMID: 21039765
amoxicillin-clavulanic acid; neonates; NONMEM; postmenstrual age; spironolactone; vancomycin
4.  External evaluation of population pharmacokinetic models of vancomycin in neonates: the transferability of published models to different clinical settings 
Vancomycin is one of the most evaluated antibiotics in neonates using modeling and simulation approaches. However no clear consensus on optimal dosing has been achieved. The objective of the present study was to perform an external evaluation of published models, in order to test their predictive performances in an independent dataset and to identify the possible study-related factors influencing the transferability of pharmacokinetic models to different clinical settings.
Published neonatal vancomycin pharmacokinetic models were screened from the literature. The predictive performance of six models was evaluated using an independent dataset (112 concentrations from 78 neonates). The evaluation procedures used simulation-based diagnostics [visual predictive check (VPC) and normalized prediction distribution errors (NPDE)].
Differences in predictive performances of models for vancomycin pharmacokinetics in neonates were found. The mean of NPDE for six evaluated models were 1.35, −0.22, −0.36, 0.24, 0.66 and 0.48, respectively. These differences were explained, at least partly, by taking into account the method used to measure serum creatinine concentrations. The adult conversion factor of 1.3 (enzymatic to Jaffé) was tested with an improvement in the VPC and NPDE, but it still needs to be evaluated and validated in neonates. Differences were also identified between analytical methods for vancomycin.
The importance of analytical techniques for serum creatinine concentrations and vancomycin as predictors of vancomycin concentrations in neonates have been confirmed. Dosage individualization of vancomycin in neonates should consider not only patients' characteristics and clinical conditions, but also the methods used to measure serum creatinine and vancomycin.
PMCID: PMC3612725  PMID: 23148919
dosing regimen; external evaluation; neonates; population pharmacokinetics; serum creatinine; vancomycin
5.  Pharmacokinetics of the time-dependent elimination of all-trans-retinoic acid in rats 
AAPS PharmSci  2004;6(1):1-9.
The time-dependent elimination kinetics of all-transretinoic acid (ATRA) has been associated with autoinduction of its metabolism and has led to the hypothesis that rapid development of acquired clinical resistance to ATRA may be prevented by coadministration of metabolic inhibitors. This study in rats was performed to investigate the pharmacokinetics and onset of timedependent elimination of ATRA, with the purpose of establishing an animal model suitable for in vivo preclinical studies of compounds capable of inhibiting ATRA metabolism. After the intravenous (IV) bolus administration of single doses of ATRA (1.60 mg kg−1 and 0.40 mg kg−1), the plasma concentration-time curves showed an accelerated decline at 180 minutes after dosing. The plasma clearance (Cl) of ATRA, determined after IV administration of a second dose (1.60 mg kg−1), at 180 minutes was greater than Cl after a single dose, thus indicating the existence of a time-dependent elimination process detectable 180 minutes after administration of the first dose. Such time-dependent elimination was confirmed by means of an IV constant-rate infusion of 0.48 mg h−1 kg−1 of ATRA during 10 hours. Peak plasma ATRA concentration was achieved at 180 minutes, after which the plasma concentration decreased to reach a much lower apparent steady-state drug concentration at 420 minutes. The area under the plasma concentration-time curve (AUC) obtained after oral administration of a second ATRA dose (1.60 mg kg−1) was ∼8% of the AUC obtained after a single oral dose; consistent with a time-dependent increase in the elimination of ATRA, as was observed after IV administration.
PMCID: PMC2750936  PMID: 18465253
all-trans-retinoic acid; time-dependent elimination; pharmacokinetic model; rat; intravenous administration; oral administration

Results 1-5 (5)