Metabolism and Disposition of the HIV-1 Protease Inhibitor Lopinavir (ABT-378) Given in Combination with Ritonavir in Rats, Dogs, and Humans

Kumar, Gondi; Jayanti, Venkata; Johnson, Marianne K.; Uchic, John T.; Thomas, Samuel; Lee, Ronald D.; Grabowski, Brian A.; Sham, Hing L.; Kempf, Dale J.; Denissen, Jon F.; Marsh, Kennan C.; Sun, Eugene; Roberts, Stanley A.

doi:10.1023/b:pham.0000041457.64638.8d

Cited by 110 publications

(111 citation statements)

References 18 publications

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“…When expressed as percentages of total serum LPV concentrations, 1.6 Ϯ 0.8% of the drug was unbound in the GDM group compared with 0.6 Ϯ 0.3 and 0.6 Ϯ 0.4% in the vehicle and insulin-treated groups, respectively ( p Ͻ 0.05). LPV plasma protein binding in the rat has been shown to be constant across a range of total LPV concentrations that encompasses all of the values observed in our study (Kumar et al, 2004).…”

Section: Lopinavir Exposure In a Rat Model Of Gestational Diabetessupporting

confidence: 70%

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Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Anger

Piquette-Miller²

2011

Drug Metab Dispos

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ABSTRACT:Lopinavir (LPV) is the preferred HIV protease inhibitor in pregnancy, but it is unknown if gestational diabetes mellitus (GDM) affects its disposition. Hepatic protein expression and plasma protein binding are altered in rodent models of GDM. Because LPV is influenced by hepatic transporters and metabolic enzymes and is highly protein bound, it was hypothesized that streptozotocininduced GDM would alter its disposition. Maternal and fetal tissues were collected from GDM rats and controls 45 min after LPV injection. In another cohort, fetuses were serially extracted 5 to 60 min after injection. LPV was quantified using liquid chromatography tandem mass spectrometry. Expression of relevant transporters, such as Multidrug resistance protein 1 (Mdr1), and cytochrome P450 3a2 (Cyp3a2), which metabolizes LPV in rodents, was measured in maternal liver via quantitative reverse transcriptase polymerase chain reaction and Western blot analysis. Expression of relevant transporters also was measured in placenta via quantitative reverse transcriptase polymerase chain reaction. Protein binding was determined by ultrafiltration. Relative to controls, we observed dramatically reduced maternal and fetal LPV exposure in GDM. Compared with controls, maternal hepatic Mdr1 and Cyp3a2 were up-regulated, and protein binding was reduced in the GDM group. Increased Mdr1-and Cyp3a2-mediated hepatobiliary clearance, coupled with a larger unbound LPV fraction, is likely to have facilitated hepatic elimination, thereby decreasing maternal and fetal exposure. Not surprisingly, up-regulation of Mdr1 and Cyp3a2's transcriptional regulator, pregnane X receptor, was demonstrated in maternal liver via Western blot analysis. Up-regulation of Mdr1 in placentas isolated from the GDM group likely also contributed to decreased fetal exposure to LPV. This study provides preclinical support for an as yet unreported drug-disease (LPV-GDM) interaction.

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Section: Lopinavir Exposure In a Rat Model Of Gestational Diabetessupporting

confidence: 70%

“…In a study of LPV metabolism and disposition in the rat, 69.5% of an intravenous LPV dose was recovered in bile after 24 h and approximately 86% of this occurred in the first 2 h (Kumar et al, 2004). In maternal liver, at 45 and 60 min, LPV concentrations in GDM were less than one third of control values.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Anger

Piquette-Miller²

2011

Drug Metab Dispos

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“…Healthy volunteers (n ϭ 16; 6 female, 3 Hispanic, and 2 black individuals) were administered 400-mg-100-mg lopinavir-ritonavir tablets twice daily to steady state, and on the morning of pharmacokinetic sampling, drug intake was observed directly and timed. The evening dose was omitted, and blood was drawn predose (0 h) and at 0.5, 1, 2, 3, 4,6,8,10,12,16,20,24,30,36,48,60, and 72 h postdose. Plasma lopinavir and ritonavir concentrations were quantified by a fully validated high-performance liquid chromatography-tandem mass spectrometry method (6), with lower limits of quantification (LLQs) of 0.005 and 0.002 mg/liter for lopinavir and ritonavir, respectively.…”

Section: Methodsmentioning

confidence: 99%

Sequential Population Pharmacokinetic Modeling of Lopinavir and Ritonavir in Healthy Volunteers and Assessment of Different Dosing Strategies

Dickinson

Boffito²,

Back

et al. 2011

Antimicrob Agents Chemother

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Nonlinear mixed-effects modeling was applied to explore the relationship between lopinavir and ritonavir concentrations over 72 h following drug cessation and also to assess other lopinavir and ritonavir dosing strategies compared to the standard 400-mg-100-mg twice-daily dose. Data from 16 healthy volunteers were included. Possible covariates influencing lopinavir and ritonavir pharmacokinetics were also assessed. Data were modeled first separately and then together by using individually predicted ritonavir pharmacokinetic parameters in the final lopinavir model. The model was evaluated by means of a visual predictive check and external validation. A maximum-effect model in which ritonavir inhibited the elimination of lopinavir best described the relationship between ritonavir concentrations and lopinavir clearance (CL/F). A ritonavir concentration of 0.06 mg/liter was associated with a 50% maximum inhibition of the lopinavir CL/F. The population prediction of the lopinavir CL/F in the absence of ritonavir was 21.6 liters/h (relative standard error, 14.0%), and the apparent volume of distribution and absorption rate constant were 55.3 liters (relative standard error, 10.2%) and 0.57 h ؊1 (relative standard error, 0.39%), respectively. Overall, 92% and 94% of the observed concentrations were encompassed by the 95% prediction intervals for lopinavir and ritonavir, respectively, which is indicative of an adequate model. Predictions of concentrations from an external data set (HIV infected) (n ‫؍‬ 12) satisfied predictive performance criteria. Simulated lopinavir exposures at lopinavirritonavir doses of 200 mg-150 mg and 200 mg-50 mg twice daily were 38% and 65% lower, respectively, than that of the standard dose. The model allows a better understanding of the interaction between lopinavir and ritonavir and may allow a better prediction of lopinavir concentrations and assessments of different dosing strategies.Coformulated lopinavir-ritonavir (Kaletra; Abbott Laboratories, Chicago, IL) has demonstrated durable treatment efficacy in HIV-infected treatment-naïve and -experienced patients (12). It is approved for use at doses of 400 mg-100 mg twice daily and additionally at 800 mg-200 mg once daily for treatment-naïve patients in Europe and the United States (1, 2). Initially, lopinavir-ritonavir was available as soft-gel capsules, which required refrigerated storage and administration with food. However, a tablet formulation has been developed, with a diminished food effect, reduced variability compared to that of soft-gel capsules, and increased heat stability, therefore no longer needing refrigeration (9). Furthermore, data suggest a trend toward an increased bioavailability of the tablets (9).Hill et al. recently performed a systematic review of 17 dose-ranging pharmacokinetic studies involving ritonavirboosted protease inhibitors in order to assess the effects of ritonavir on different protease inhibitors and vice versa. Lopinavir concentrations were significantly increased in the presence of ritonavir and were c...

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“…Due to limited oral bioavailability and poor pharmacokinetics of many of the currently available PIs, additional efforts have been made to design more potent PIs with improved pharmacokinetic properties. Lopinavir (LVR), an analog of ritonavir (RVR) is a potent inhibitor of wild type and mutant HIV protease (Ki =1.3-28 pM) (Kumar et al, 2004). Its structure is outlined in Fig.1.…”

Section: Introductionmentioning

confidence: 99%

“…The low oral bioavailability of LVR was attributed to high first-pass metabolism (Kumar et al, 2004). In vitro investigations with human liver microsomes have shown that cytochrome P450 3A plays a predominant role in the metabolism of LVR.…”

Section: Introductionmentioning

confidence: 99%

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Agarwal

Pal

Mitra

2007

International Journal of Pharmaceutics

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Polarized epithelial non-human (canine) cell lines stably transfected with human or murine complementary DNA (cDNA) encoding for various efflux transporters (P-gp/MDR1, MRP1, MRP2, and Bcrp1) were used to study transepithelial transport of Lopinavir (LVR) and compare results with the MDCKII-Wild type cells. These transmembrane proteins cause multidrug resistance by decreasing the total intracellular accumulation of drugs. Lopinavir efflux was directional and was completely inhibited by MK-571, a selective MRP family inhibitor in the MDCKII-MRP2 cell line. Similarly, LVR efflux was also inhibited by P-gp inhibitors P-gp 4008 and GF120918 in the MDCKII-MDR1 cell line. The efflux ratios (Efflux rate/ Influx rate) of LVR in the absence of any efflux inhibitors in the MDCK-Wild type, MDCKII-MDR1, MDCKII-MRP1 and MDCKII-MRP2 cell monolayers were 1.32, 4.91, 1.26 and 2.89 respectively. The MDCKII-MDR1 and MDCKII-MRP2 cells have significantly increased LVR efflux ratio relative to the parental cells due to the apically directed transport by MDR1 and MRP2 respectively. The efflux ratios in MRP2 and MDR1 transfected cell lines were close to unity in the presence of MK-571 and P-gp 4008 respectively; indicating that LVR efflux by MRP2 and P-gp was completely inhibited by their selective inhibitors. MDCKII-MRP1 cells did not exhibit a significant reduction in the LVR efflux relative to the parental cells, indicating that LVR is not a good substrate for MRP1. Transport studies across MDCKII-Bcrp1 cells indicated that LVR is not transported by Bcrp1 and is not a substrate for this efflux protein. In conclusion, this study presents direct evidence that LVR is effluxed by both P-gp and MRP2 which may contribute to its poor oral bioavailability and limited penetration into the CNS. KeywordsMDCKII-MDR1; MDCKII-MRP2; MDCKII-MRP1; MDCKII-Bcrp1; MDCKII-WT; Pglycoprotein (P-gp); multidrug resistance protein (MRP); breast cancer resistance protein (BCRP); Lopinavir (LVR); uptake; transport; permeability; efflux ratio (ER)

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Metabolism and Disposition of the HIV-1 Protease Inhibitor Lopinavir (ABT-378) Given in Combination with Ritonavir in Rats, Dogs, and Humans

Cited by 110 publications

References 18 publications

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Sequential Population Pharmacokinetic Modeling of Lopinavir and Ritonavir in Healthy Volunteers and Assessment of Different Dosing Strategies

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

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