Evaluation of partial area under the concentration time curve to estimate midazolam apparent oral clearance for cytochrome P450 3A phenotyping

2013 ◽  
Vol 28 (4) ◽  
Author(s):  
Wei Tai ◽  
Sheryl L. Gong ◽  
Shirley M. Tsunoda ◽  
Howard E. Greenberg ◽  
J. Christopher Gorski ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Oral Clearance ◽  
Cytochrome P450 3A ◽  
Time Curve ◽  
Apparent Oral Clearance ◽  
Concentration Time ◽  
Partial Area

scholarly journals Rifampin Greatly Reduces the Plasma Concentrations of Intravenous and Oral Oxycodone

2009 ◽  
Vol 110 (6) ◽  
pp. 1371-1378 ◽  
Author(s):  
Tuija H. Nieminen ◽  
Nora M. Hagelberg ◽  
Teijo I. Saari ◽  
Antti Pertovaara ◽  
Mikko Neuvonen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Cytochrome P450 3A ◽  
Time Curve ◽  
Cold Pain ◽  
Visual Analog Scales ◽  
Concentration Time ◽  
Heat Pain Threshold ◽  
Oxycodone Hydrochloride

Background Oxycodone is a mu-opioid receptor agonist that is metabolized mainly in the liver by cytochrome P450 3A and 2D6 enzymes. Rifampin is a strong inducer of several drug-metabolizing enzymes. The authors studied the interaction of rifampin with oxycodone. Their hypothesis was that rifampin enhances the CYP3A-mediated metabolism of oxycodone and attenuates its pharmacologic effect. Methods The protocol was a four-session, paired crossover. Twelve volunteers were given 600 mg oral rifampin or placebo once daily for 7 days. Oxycodone was given on day 6. In the first part of the study, 0.1 mg/kg oxycodone hydrochloride was given intravenously. In the second part of the study, 15 mg oxycodone hydrochloride was given orally. Concentrations of oxycodone and its metabolites noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Psychomotor effects were characterized for 12 h by several visual analog scales. Analgesic effects were characterized by measuring the heat pain threshold and cold pain sensitivity. Results Rifampin decreased the area under the oxycodone concentration-time curve of intravenous and oral oxycodone by 53% and 86%, respectively (P < 0.001). Oral bioavailability of oxycodone was decreased from 69% to 21% (P < 0.001). Rifampin greatly increased the plasma metabolite-to-parent drug ratios for noroxycodone and noroxymorphone (P < 0.001). Pharmacologic effects of oral oxycodone were attenuated. Conclusions Induction of cytochrome P450 3A by rifampin reduced the area under the oxycodone concentration-time curve of intravenous and oral oxycodone. The pharmacologic effects of oxycodone were modestly attenuated. To maintain adequate analgesia, dose adjustment of oxycodone may be necessary, when used concomitantly with rifampin.

scholarly journals Pharmacokinetic Interactions of Maraviroc with Darunavir-Ritonavir, Etravirine, and Etravirine-Darunavir-Ritonavir in Healthy Volunteers: Results of Two Drug Interaction Trials

2011 ◽  
Vol 55 (5) ◽  
pp. 2290-2296 ◽  
Author(s):  
Thomas N. Kakuda ◽  
Samantha Abel ◽  
John Davis ◽  
Julia Hamlin ◽  
Monika Schöller-Gyüre ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Volunteers ◽  
Potent Inhibitor ◽  
Cytochrome P450 3A ◽  
Short Term ◽  
Two Phase ◽  
Time Curve ◽  
Safety Issues ◽  
Concentration Time ◽  
Crossover Studies

ABSTRACTThe effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC12) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC12by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC123.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir, etravirine, or etravirine-darunavir-ritonavir. Maraviroc should be dosed at 600 mg b.i.d. with etravirine in the absence of a potent inhibitor of cytochrome P450 3A (CYP3A) (i.e., a boosted protease inhibitor) or at 150 mg b.i.d. when coadministered with darunavir-ritonavir with or without etravirine.

scholarly journals Pharmacokinetics of Lopinavir-Ritonavir with and without Nonnucleoside Reverse Transcriptase Inhibitors in Ugandan HIV-Infected Adults

2010 ◽  
Vol 54 (7) ◽  
pp. 2965-2973 ◽  
Author(s):  
C. Kityo ◽  
A. S. Walker ◽  
L. Dickinson ◽  
F. Lutwama ◽  
J. Kayiwa ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Geometric Mean ◽  
Oral Clearance ◽  
Reverse Transcriptase Inhibitors ◽  
Time Curve ◽  
Nonnucleoside Reverse Transcriptase Inhibitors ◽  
Concentration Time ◽  
Half Dose ◽  
Trial Participants ◽  
Dose Tablet

ABSTRACT We evaluated the pharmacokinetics of lopinavir-ritonavir with and without nonnucleoside reverse transcriptase inhibitors (NNRTIs) in Ugandan adults. The study design was a three-period crossover study (3 tablets [600 mg of lopinavir/150 mg of ritonavir {600/150 mg}], 4 capsules [533/133 mg], and 2 tablets [400/100 mg] twice a day [BD]; n = 40) of lopinavir-ritonavir with NNRTIs and a parallel one-period study (2 tablets BD; n = 20) without NNRTIs. Six-point pharmacokinetic sampling (0, 2, 4, 6, 8, and 12 h) was undertaken after observed intake with a standardized breakfast. Ugandan DART trial participants receiving efavirenz (n = 20), nevirapine (n = 18), and no NNRTI (n = 20) had median ages of 41, 35, and 37 years, respectively, and median weights of 60, 64, and 63 kg, respectively. For the no-NNRTI group, the geometric mean (percent coefficient of variation [%CV]) lopinavir area under the concentration-time curve from 0 to 12 h (AUC0-12) was 110.1 (34%) μg·h/liter. For efavirenz, the geometric mean lopinavir AUC0-12 (%CV) values were 91.8 μg·h/liter (58%), 65.7 μg·h/liter (39%), and 54.0 μg·h/liter (65%) with 3 tablets, 4 capsules, and 2 tablets BD, respectively, with corresponding (within-individual) geometric mean ratios (GMR) for 3 and 2 tablets versus 4 capsules of 1.40 (90% confidence interval [CI], 1.18 to 1.65; P = 0.002) and 0.82 (90% CI, 0.68 to 0.99; P = 0.09), respectively, and the apparent oral clearance (CL/F) values were reduced by 58% and 1%, respectively. For nevirapine, the geometric mean lopinavir AUC0-12 (%CV) values were 112.9 μg·h/liter (30%), 68.1 μg·h/liter (53%), and 61.5 μg·h/liter (52%), respectively, with corresponding GMR values of 1.66 (90% CI, 1.46 to 1.88; P < 0.001) and 0.90 (90% CI, 0.77 to 1.06; P = 0.27), respectively, and the CL/F was reduced by 57% and 7%, respectively. Higher values for the lopinavir concentration at 12 h (C 12) were observed with 3 tablets and efavirenz-nevirapine (P = 0.04 and P = 0.0005, respectively), and marginally lower C 12 values were observed with 2 tablets and efavirenz-nevirapine (P = 0.08 and P = 0.26, respectively). These data suggest that 2 tablets of lopinavir-ritonavir BD may be inadequate when dosed with NNRTIs in Ugandan adults, and the dosage should be increased by the addition of an additional adult tablet or a half-dose tablet (100/25 mg), where available.

scholarly journals Oral Cimetidine Prolongs Clarithromycin Absorption

1998 ◽  
Vol 42 (7) ◽  
pp. 1578-1580 ◽  
Author(s):  
Guy W. Amsden ◽  
Kit L. Cheng ◽  
Charles A. Peloquin ◽  
Anne N. Nafziger
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
Potential Interaction ◽  
Oral Clearance ◽  
Time Curve ◽  
Concentration Time ◽  
Oral Cimetidine

ABSTRACT The present study was conducted to identify any potential interaction between oral cimetidine and clarithromycin. Twelve healthy subjects were administered single doses of clarithromycin alone and with oral cimetidine dosed to steady state. Cimetidine prolonged the absorption of clarithromycin, as evidenced by decreased peak concentrations of both clarithromycin and 14-OH-clarithromycin (14OHC) in serum (46 and 43%, respectively), a delay in the formation of 14OHC (increase of 68%), and increases in both of their half-lives (75 and 82%, respectively), despite no changes in total oral clearance or area under the concentration-time curve for either compound. No mechanism for this interaction has been identified.

Omeprazole limited sampling strategies to predict area under the concentration–time curve ratios: implications for cytochrome P450 2C19 and 3A phenotyping

2011 ◽  
Vol 68 (4) ◽  
pp. 407-413 ◽  
Author(s):  
Eileen B. Lawson ◽  
Jerry C. Wu ◽  
R. Michael Baldwin ◽  
Magnus Ingelman-Sundberg ◽  
Staffan Rosenborg ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Sampling Strategies ◽  
Time Curve ◽  
Limited Sampling ◽  
Concentration Time ◽  
Cytochrome P450 2C19

Limitations of S-Warfarin Truncated Area Under the Concentration-Time Curve to Predict Cytochrome P450 2c9 Activity

2012 ◽  
Vol 6 (2) ◽  
pp. 94-101 ◽  
Author(s):  
Jerry C. Wu ◽  
Anne N. Nafziger ◽  
Joseph S. Bertino ◽  
Joseph D. Ma
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 2C9 ◽  
Time Curve ◽  
Concentration Time

scholarly journals Lack of Indinavir Effects on Methadone Disposition Despite Inhibition of Hepatic and Intestinal Cytochrome P4503A (CYP3A)

2012 ◽  
Vol 116 (2) ◽  
pp. 432-447 ◽  
Author(s):  
Evan D. Kharasch ◽  
Pamela Sheffels Bedynek ◽  
Christine Hoffer ◽  
Alysa Walker ◽  
Dale Whittington
Keyword(s):  
Plasma Concentration ◽  
Drug Interactions ◽  
Plasma Concentrations ◽  
Antiretroviral Drugs ◽  
Cyp3a Activity ◽  
Oral Clearance ◽  
Hepatic Extraction ◽  
Time Curve ◽  
Apparent Oral Clearance ◽  
First Pass

Background Methadone disposition and pharmacodynamics are highly susceptible to interactions with antiretroviral drugs. Methadone clearance and drug interactions have been attributed to cytochrome P4503A4 (CYP3A4), but actual mechanisms are unknown. Drug interactions can be clinically and mechanistically informative. This investigation assessed effects of the protease inhibitor indinavir on methadone pharmacokinetics and pharmacodynamics, hepatic and intestinal CYP3A4/5 activity (using alfentanil), and intestinal transporter activity (using fexofenadine). Methods Twelve healthy volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone. This was repeated after 2 weeks of indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by miosis. Results Indinavir significantly inhibited hepatic and first-pass CYP3A activity. Intravenous alfentanil systemic clearance and hepatic extraction were reduced to 40-50% of control, apparent oral clearance to 30% of control, and intestinal extraction decreased by half, indicating 50% and 70% inhibition of hepatic and first-pass CYP3A activity. Indinavir increased fexofenadine area under the plasma concentration-time curve 3-fold, suggesting significant P-glycoprotein inhibition. Indinavir had no significant effects on methadone plasma concentrations, methadone N-demethylation, systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Methadone plasma concentration-effect relationships were unaffected by indinavir. Conclusions Despite significant inhibition of hepatic and intestinal CYP3A activity, indinavir had no effect on methadone N-demethylation and clearance, suggesting little or no role for CYP3A in clinical disposition of single-dose methadone. Inhibition of gastrointestinal transporter activity had no influence of methadone bioavailability.

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