Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir*

Hsu, Ann; Granneman, G. Richard; Cao, Guoliang; Carothers, Lori; El-Shourbagy, Tawalkol; Baroldi, Paolo; Erdman, Keith; Brown, Frances C.; Sun, Eugene; Leonard, John M.

doi:10.1016/s0009-9236(98)90041-8

Cited by 153 publications

(102 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They exhibit extensive pharmacokinetic (PK) interactions (Merry et al, 1997;Hsu et al, 1998b;Jarvis et al, 1998), but the degree to which those interactions occur at the level of hepatic metabolism, gut metabolism, or gut efflux transporters is still uncertain. Adult AIDS clinical trial group study 378 (ACTG 378), involving staggered versus simultaneous administration of the three PIs, was designed to shed light on these issues.…”

Section: Introductionmentioning

confidence: 99%

Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration

Blaschke

Flexner³

et al. 2002

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Eighteen healthy human immunodeficiency virus-negative subjects participated in an open-label, six-period, incomplete Latinsquare crossover pharmacokinetic study. Each subject received two of the three possible pair-wise combinations of single-dose oral ritonavir (R) (400 mg), nelfinavir (N) (750 mg), and saquinavir (S) (800 mg), each pair on three occasions (simultaneous or staggered administration), each occasion at least 2 days after the last. A model-based analysis reveals the following major drug interactions under the conditions of this study: 1) R given simultaneously with S decreases S hepatic intrinsic clearance almost 50-fold relative to that predicted for S given alone and increases its gut bioavailability 90% (but decreases its rate of absorption 40%) relative to when N is given simultaneously; 2) N given simultaneously with S decreases S hepatic intrinsic clearance 10-fold relative to that predicted for S given alone; and 3) R inhibits S hepatic intrinsic clearance even after R plasma levels have become undetectable (>48 h after dosing), implying that R, when used as a pharmacokinetic enhancer, can be dosed less frequently than might be predicted from the duration of detectable systemic concentrations.Protease inhibitors (PIs 1 ) ritonavir (R), nelfinavir (N), and saquinavir (S) are primarily metabolized by CYP3A4 (and partially by other cytochromes P450) in the liver (Eagling et al., 1997;Fitzsimmons and Collins, 1997;Hsu et al., 1998a;Kim et al., 1998;Washington et al., 1998). They exhibit extensive pharmacokinetic (PK) interactions (Merry et al., 1997;Hsu et al., 1998b;Jarvis et al., 1998), but the degree to which those interactions occur at the level of hepatic metabolism, gut metabolism, or gut efflux transporters is still uncertain. Adult AIDS clinical trial group study 378 (ACTG 378), involving staggered versus simultaneous administration of the three PIs, was designed to shed light on these issues. The findings with respect to changes of AUC (proportional to the ratio of systemic clearance to bioavailability) are reported elsewhere (C. B. Washington, C. Flexner, L. B. Sheiner, S. L. Rosenkranz, M.A. Jacobson, T. F. Blaschke, submitted); they are considerable. This paper extends those findings by presenting a physiologically based population pharmacokinetic model applied to the full ACTG 378 data to assess and quantify the gut versus hepatic mechanisms responsible for the AUC changes and for any other PK interactions. Materials and MethodsData Source. ACTG 378 was an open-label, Latin-square design study of the effect of staggered versus simultaneous dosing on the PK profiles of the following three protease inhibitors: R, N, and S (we use the symbols R, N, S to refer not only to the drugs but to their concentrations; context should make clear which meaning is intended). A total of 18 human immunodeficiency virus-negative healthy volunteers participated in the study, and each was randomized to receive two of the three pairs (N ϩ R, N ϩ S, and R ϩ S) in two series of three occasions. T...

show abstract

Section: Introductionmentioning

confidence: 99%

Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration

Blaschke

Flexner³

et al. 2002

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…Its slope signifies the extent of the changes. The shaded areas indicate the consistency of exposure changes induced by a specific parameter change, which provides the evidence for selecting the candidates for the example in the study by Hsu et al [17] 1. A linear, one-compartment model with firstorder elimination was assumed.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7][8] In cases of the third category, C max has larger fold changes compared with AUC. [9][10][11][12][13][14][15][16][17][18] It is interesting to note that rosuvastatin in three different studies with three different concomitant medications (gemfibrozil, [6] lopinavir/ ritonavir [7] and ciclosporin, [8] respectively) showed similar pattern with C max having higher fold changes compared to AUC fold changes, although the absolute fold changes were different (2.21, 4.7 and 10.6 for C max , respectively). On the other hand, gemfibrozil as a COMED in another study [15] caused AUC and C max fold changes of repaglinide following another pattern: AUC was much higher than C max (7 vs 2).…”

Section: Introductionmentioning

confidence: 99%

“…If the net effect on AUC is the product of first-pass and post-absorptive inhibition, then the latter corresponding inhibition can be estimated to be 4 expressed as the AUC fold change, which is relatively small and very close to the reported estimate. [17] It is important to understand the nature of DDI in order to prevent its adverse consequences if any. When a DDI is metabolism based, it is critical to identify whether the DDI occurs at pre-systemic level or systemic level.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Drug-Drug Interaction Pattern Recognition

Duan

2010

Drugs R D

View full text Add to dashboard Cite

Background and Objective: Drug-drug interaction (DDI) is an important aspect of drug development, especially for safety. When a drug is used concomitantly with other drug(s), one of the major concerns is the change of exposures, including the rate and extent of drug absorption, distribution, metabolism and elimination. To address the concerns, a common practice is to measure and report the differences between the exposure in the presence and in the absence of concomitant medication (COMED). The area under the plasma concentration versus time curve (AUC), maximum plasma concentration (C max ) and time to reach the C max (t max ) changes are usually measured in DDI studies. A usual observation is the different extents of changes among AUC, C max and t max , which may raise concerns in certain therapeutic areas or some special agents. The objective of this study was to investigate the variation among changes of AUC, C max and t max in DDI studies, and its pharmacokinetic manifestation. Data Sources: Based on a list of DDI results from the literature, with the assumptions that the primary parameters of a drug of interest were altered during a DDI, two sets of simulated data were generated according to a single oral dose, one-compartment model. The first set including 24 cases with different half-lives and absorption constants (k a ) considered the exposure changes upon independent variation of bioavailability (F), clearance (CL), volume of distribution (V d ) and k a up to 50-fold increases or decreases. The second set considered the exposure changes with simultaneous variation of F, CL, V d , and k a within 5-fold range (increase or decrease) for a case selected from the first set. Study Selection, Data Extraction and Synthesis: Parameter fold changes (defined in a fashion showing fold increase or fold decreases, including CL fold change, F fold change, V d fold change and k a fold change) and exposure changes (AUC fold change, C max fold change, t max fold change and fold change difference [AUC fold change -C max fold change]) were used to generate plots demonstrating various relationships between parameter fold changes and exposure changes. Based on the observations that AUC was influenced by CL and F, C max was affected by all four parameters, t max was mainly determined by CL and k a , F did little for t max and k a was unrelated to AUC, a chart was created for DDI pattern recognition.

show abstract

“…Because SQV had a low oral bioavailability (Perry and Noble, 1998) and a short elimination half-life (Hsu et al, 1998), SQV was administered twice daily for 28 days with a minimum of 8 hr between the two treatments. The chemical solutions were prepared as 15, 30, and 60 mg/mL, and the resulted SQV treatment doses were 300, 600, and 1200 mg/kg/day, respectively.…”

Section: Animals and Animal Exposurementioning

confidence: 99%

Immunomodulation in female B₆C₃F₁mice following treatment with the HIV protease inhibitor saquinavir for 28 days by gavage

Guo

Germolec

Roesh

et al. 2010

Journal of Immunotoxicology

View full text Add to dashboard Cite

Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir*

Cited by 153 publications

References 24 publications

Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration

Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration

Drug-Drug Interaction Pattern Recognition

Immunomodulation in female B₆C₃F₁mice following treatment with the HIV protease inhibitor saquinavir for 28 days by gavage

Contact Info

Product

Resources

About

Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir*

Cited by 153 publications

References 24 publications

Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration

Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration

Drug-Drug Interaction Pattern Recognition

Immunomodulation in female B6C3F1mice following treatment with the HIV protease inhibitor saquinavir for 28 days by gavage

Contact Info

Product

Resources

About

Immunomodulation in female B₆C₃F₁mice following treatment with the HIV protease inhibitor saquinavir for 28 days by gavage