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1.  Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability 
Introduction
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.
Discussion
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.
Conclusions
This review presents a wide description of NNRTIs, providing useful information for researchers interested in this field, both in clinical use and in research.
doi:10.7448/IAS.16.1.18567
PMCID: PMC3764307  PMID: 24008177
human immunodeficiency virus; non-nucleoside reverse transcriptase inhibitors; nevirapine; delavirdine; efavirenz; etravirine; rilpivirine; next-generation non-nucleoside reverse transcriptase inhibitors
2.  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.
doi:10.1208/ps060101
PMCID: PMC2750936  PMID: 18465253
all-trans-retinoic acid; time-dependent elimination; pharmacokinetic model; rat; intravenous administration; oral administration

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