Lopinavir

Hurst, Miriam; Faulds, Diana

doi:10.2165/00003495-200060060-00009

Cited by 110 publications

(54 citation statements)

References 7 publications

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“…These results were not related to the reduced plasma concentrations of lopinavir obtained, as they were comparable to those previously obtained and described (6). The plasma indinavir concentrations obtained here were also comparable to those previously published (5).…”

supporting

confidence: 93%

Differential Diffusions of Indinavir and Lopinavir in Genital Secretions of Human Immunodeficiency Virus-Infected Women

Launay¹,

Tod

Louchahi

et al. 2004

Antimicrob Agents Chemother

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Plasma and cervicovaginal secretion (CVS) samples were collected from 19 human immunodeficiency virus type 1-infected women on lopinavir-or indinavir-containing regimens. Lopinavir and indinavir were detectable in 29 and 93% of CVS samples, respectively, a finding that may be ascribed to these drugs' differences in protein binding and pK a . The relationship between lopinavir and indinavir pharmacodynamics and viral evolution in the female genital tract should be assessed over time.Differential viral load suppression and rate of emergence of drug resistance-associated viral mutations have been observed between blood and genital compartments, a fact which has possibly been related to inadequate penetration of antiretroviral drugs into sanctuaries (3,4,9,11,12,14,15). Numerous studies have evaluated the penetration of antiretrovirals into the male genital tract (7,8,16,17). In contrast, data on the diffusion of antiretrovirals in the female genital tract are scarce, but preliminary results evidenced major differences between drugs in terms of detection in cervicovaginal secretions (CVS) (8,14). Protease inhibitors (PIs) exhibit variable protein binding capacities and physicochemical properties, which might influence PI diffusion into the female genital tract. We thus decided to compare the pharmacokinetics of indinavir alone or combined with ritonavir and that of lopinavir-ritonavir in the plasma and genital secretions of human immunodeficiency virus type 1 (HIV-1)-infected women.HIV-1-infected women who were on a lopinavir-or indinavir-containing regimen for a minimum of 4 weeks were recruited between October 2001 and July 2002. They had no symptoms of genital infection and no genital bleeding during the 5 days preceding the visit and were asked to avoid sexual intercourse and intravaginal medications within 2 days before sample processing. To assess whether the patients were adherent to their treatment, they were asked to fill out a simple self-administered questionnaire regarding their drug intake during the 4 days preceding the study visit. After the introduction of a speculum, genital secretions were collected by a lavage performed with 3 ml of phosphate-buffered saline, pH 7.2, containing a 10 mM concentration of lithium chloride. Within 15 min after collection of the genital secretion, a blood sample was taken for the measurement of plasma lopinavir or indinavir concentration. None of the women had taken drugs susceptible to interaction with the metabolism of either indinavir or lopinavir. For each woman, samples were precisely collected just before and 3 to 4 h after intake of the last drug for measurements of 12-h trough and peak plasma concentrations simultaneously with that of drug levels in genital secretions. Both peak and trough concentrations were measured at two different visits separated by 1 to 3 months. The study protocol was approved by the Ethics Committee of the Pitié-Salpêtrière Hospital, Paris, France, and signed informed consent was obtained from all women. Measurements of antiretroviral d...

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supporting

confidence: 93%

Differential Diffusions of Indinavir and Lopinavir in Genital Secretions of Human Immunodeficiency Virus-Infected Women

Launay¹,

Tod

Louchahi

et al. 2004

Antimicrob Agents Chemother

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“…Similar pharmacokinetic interactions are known to occur when lopinavir is combined with efavirenz (3) and amprenavir (29), but these covariates did not provide a significant decrease in the objective function, probably because not enough samples were involved. Another important pharmacokinetic interaction is the increase in lopinavir exposure provided by ritonavir (15). However, the use of the ritonavir concentration as a covariate in the model was not investigated in the present study, as the study design did not allow it.…”

Section: Discussionmentioning

confidence: 99%

Population Analysis of Weight-, Age-, and Sex-Related Differences in the Pharmacokinetics of Lopinavir in Children from Birth to 18 Years

Jullien

Urien

Hirt

et al. 2006

Antimicrob Agents Chemother

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The pharmacokinetics of lopinavir were investigated by the use of a population approach performed with the nonlinear mixed effect modeling program NONMEM and 157 children ranging in age from 3 days to 18 years. The pharmacokinetics of lopinavir were well described by a one-compartment model in which the absorption and the elimination rate constants were equal. Typical population estimates of the apparent volume of distribution (V/F) and plasma clearance (CL/F) were 24.6 liters and 2.58 liters/h, respectively. The lopinavir V/F and CL/F were both related to body weight (BW), with an important increase in weight-normalized CL/F for the lowest BW. Combined treatment with lopinavir and nevirapine was found to increase the CL/F. The lopinavir CL/F was also age and sex related, as a 39% increase was observed after the age of 12 years for boys compared to the CL/F for girls. The consequences of these pharmacokinetic discrepancies and the necessity to modify the currently recommended dosage regimen should be further investigated.Lopinavir is a protease inhibitor (PI) used for the treatment of human immunodeficiency virus (HIV) infection in children and adults. Lopinavir can be administered to children older than 6 months of age by the use of a liquid formulation as well as by the use of a solid oral formulation, both of which contain ritonavir for pharmacokinetic enhancement, at recommended lopinavir/ritonavir doses of 12/3 mg/kg of body weight (BW) twice daily (BID) for children with BWs between 7 and 14 kg and 10/2.5 mg/kg BID for children with BWs between 15 and 40 kg. For children with body weights greater than 40 kg, the 400/100-mg BID adult dosage regimen is recommended. Children younger than 6 months of age were not investigated in previously published studies (3,27). This lack of data can explain to some extent why lopinavir is not recommended for use in children younger than age 6 months. Nevertheless, there are clinical situations, such as the presence of a viral strain less sensitive to the other antiretrovirals, which could require the administration of lopinavir to very young children. Another pediatric population for which pharmacokinetic data are lacking is children with BWs greater than 40 kg. However, this lack of data for adolescents is a very common phenomenon and is relevant not only to lopinavir. Frequently, adolescents are considered similar to adults from a pharmacokinetic point of view, which explains why adolescents often receive the recommended adult dosage regimen. However, adolescence is characterized by physiological and hormonal changes (26, 30), the possible consequences of which on the pharmacokinetics and metabolism of drugs are still unknown. Because pharmacokinetic data for children younger than age 6 months and adolescents are lacking, the relationships between lopinavir pharmacokinetic parameters and the individual characteristics of children are also not known. These relationships are nevertheless important for optimization of the lopinavir dosage regimen, as several studies perform...

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“…Many of these would be expected to be similar to those encountered when attempting to predict drug-drug interactions resulting from P450 inhibition, including selection of the most appropriate measure of in vivo inhibitor concentration (free drug versus total drug and different inhibitor concentrations at the enzyme active site from in (Hurst and Faulds, 2000). b Plasma protein unbound drug fraction F u , maximum plasma drug concentration (C max ), and plasma drug concentration at trough (C min ) values were from literature reports (Flexner, 2000;de Maat et al, 2003;Goldsmith and Perry, 2003).…”

Section: Inhibition Of Bilirubin Glucuronidation By Hiv Protease Inhimentioning

confidence: 99%

In Vitro Inhibition of Udp Glucuronosyltransferases by Atazanavir and Other Hiv Protease Inhibitors and the Relationship of This Property to in Vivo Bilirubin Glucuronidation

Zhang¹,

Chando²,

Everett³

et al. 2005

Drug Metab Dispos

266

197

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ABSTRACT:Several human immunodeficiency virus (HIV) protease inhibitors, including atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, were tested for their potential to inhibit uridine 5-diphospho-glucuronosyltransferase (UGT) activity. Experiments were performed with human cDNA-expressed enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) as well as human liver microsomes.All of the protease inhibitors tested were inhibitors of UGT1A1, UGT1A3, and UGT1A4 with IC 50 values that ranged from 2 to 87 M. The IC 50 values found for all compounds for UGT1A6, 1A9, and 2B7 were >100 M. The inhibition (IC 50 ) of UGT1A1 was similar when tested against the human cDNA-expressed enzyme or human liver microsomes for atazanavir, indinavir, and saquinavir (2.4, 87, and 7.3 M versus 2.5, 68, and 5.0 M, respectively). By analysis of the double-reciprocal plots of bilirubin glucuronidation activities at different bilirubin concentrations in the presence of fixed concentrations of inhibitors, the UGT1A1 inhibition by atazanavir and indinavir was demonstrated to follow a linear mixed-type inhibition mechanism (K i ‫؍‬ 1.9 and 47.9 M, respectively). These results suggest that a direct inhibition of UGT1A1-mediated bilirubin glucuronidation may provide a mechanism for the reversible hyperbilirubinemia associated with administration of atazanavir as well as indinavir. In vitro-in vivo scaling with [I]/K i predicts that atazanavir and indinavir are more likely to induce hyperbilirubinemia than other HIV protease inhibitors studied when a free C max drug concentration was used. Our current study provides a unique example of in vitro-in vivo correlation for an endogenous UGT-mediated metabolic pathway.The HIV protease is an essential enzyme that cuts the viral gag-pol polyprotein into its functional subunits. Atazanavir, indinavir, saquinavir, lopinavir, ritonavir, and nelfinavir are HIV protease inhibitors. The structures of these HIV protease inhibitors are shown in Fig. 1. As opposed to atazanavir, which is an azapeptide protease inhibitor (Goldsmith and Perry, 2003), other listed HIV protease inhibitors are peptidomimetics sharing the same structural determinant, i.e., a hydroxyethylene or a hydroxyethylamine moiety, which makes them nonscissile HIV protease substrate analogs. These HIV protease inhibitors are metabolized primarily by hepatic CYP3A enzymes, and they are also inhibitors of CYP3A enzymes (Flexner, 2000;de Maat et al., 2003;Goldsmith and Perry, 2003;Ernest et al., 2005). All of these HIV protease inhibitors have a high protein binding (Ͼ98%), except indinavir and atazanavir, which have a protein binding of 60 and 86%, respectively. Most of the HIV protease inhibitors are bound to ␣1-acid glycoprotein instead of albumin (de Maat et al., 2003). There are no literature reports indicating that HIV protease inhibitors are good substrates for human UGT enzymes, although there is evidence to support indinavir as a substrate of UGTs (Balani et al., 1996).Glucuronidation represents a major pathway for the elimin...

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Lopinavir

Cited by 110 publications

References 7 publications

Differential Diffusions of Indinavir and Lopinavir in Genital Secretions of Human Immunodeficiency Virus-Infected Women

Differential Diffusions of Indinavir and Lopinavir in Genital Secretions of Human Immunodeficiency Virus-Infected Women

Population Analysis of Weight-, Age-, and Sex-Related Differences in the Pharmacokinetics of Lopinavir in Children from Birth to 18 Years

In Vitro Inhibition of Udp Glucuronosyltransferases by Atazanavir and Other Hiv Protease Inhibitors and the Relationship of This Property to in Vivo Bilirubin Glucuronidation

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