scholarly journals Evaluation of Doravirine Pharmacokinetics When Switching from Efavirenz to Doravirine in Healthy Subjects

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Ka Lai Yee ◽  
Rosa I. Sanchez ◽  
Patrice Auger ◽  
Rachael Liu ◽  
Li Fan ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Healthy Subjects ◽  
Geometric Mean ◽  
Transcriptase Inhibitor ◽  
Open Label ◽  
Genetic Barrier ◽  
Fixed Sequence ◽  
Time Curve ◽  
Cyp3a4 Substrate

ABSTRACT Doravirine is a novel, potent nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of patients with human immunodeficiency virus type 1 (HIV-1) infection that demonstrates a high genetic barrier to resistance and that has been well tolerated in studies to date. Doravirine is a candidate for patients switching from less-well-tolerated NNRTIs, such as efavirenz. While doravirine is a cytochrome P450 3A4 (CYP3A4) substrate, efavirenz induces CYP3A4; therefore, the pharmacokinetics of both drugs following a switch from efavirenz to doravirine were assessed. This was a 3-period, fixed-sequence, open-label study. Healthy adults were dosed with doravirine at 100 mg for 5 days once daily (QD) (period 1). Following a 7-day washout, efavirenz was administered at 600 mg QD for 14 days (period 2). Subsequently, doravirine was administered at 100 mg QD for 14 days (period 3). Blood samples were collected for pharmacokinetic analyses. Twenty healthy subjects were enrolled, and 17 completed the study. One day after efavirenz cessation, the doravirine area under the concentration-time curve from predosing to 24 h postdosing (AUC0–24), maximum observed plasma concentration (C max), and observed plasma concentration at 24 h postdosing (C 24) were reduced by 62%, 35%, and 85%, respectively, compared with the values with no efavirenz pretreatment. These decreases recovered to 32%, 14%, and 50% for AUC0–24, C max, and C 24, respectively, by day 14 after efavirenz cessation. The doravirine C 24 reached projected therapeutic trough concentrations, based on in vitro efficacy, on day 2 following efavirenz cessation. Geometric mean efavirenz concentrations were 3,180 ng/ml on day 1 and 95.7 ng/ml on day 15, and efavirenz was present at therapeutic concentrations (>1,000 ng/ml) until day 4. Though doravirine exposure was transiently decreased following efavirenz treatment cessation, dose adjustment may not be necessary to maintain therapeutic concentrations of at least one drug during switching in a virologically suppressed population.

scholarly journals Lack of a Significant Drug Interaction between Raltegravir and Tenofovir

2008 ◽  
Vol 52 (9) ◽  
pp. 3253-3258 ◽  
Author(s):  
Larissa A. Wenning ◽  
Evan J. Friedman ◽  
James T. Kost ◽  
Sheila A. Breidinger ◽  
Jon E. Stek ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Peak Plasma ◽  
Geometric Mean ◽  
Integrase Inhibitor ◽  
Substantial Effect ◽  
Open Label ◽  
Time Curve ◽  
Once Daily ◽  
Hiv 1

ABSTRACT Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase inhibitor with potent in vitro activity (95% inhibitory concentration of 31 nM in 50% human serum). This article reports the results of an open-label, sequential, three-period study of healthy subjects. Period 1 involved raltegravir at 400 mg twice daily for 4 days, period 2 involved tenofovir disoproxil fumarate (TDF) at 300 mg once daily for 7 days, and period 3 involved raltegravir at 400 mg twice daily plus TDF at 300 mg once daily for 4 days. Pharmacokinetic profiles were also determined in HIV-1-infected patients dosed with raltegravir monotherapy versus raltegravir in combination with TDF and lamivudine. There was no clinically significant effect of TDF on raltegravir. The raltegravir area under the concentration time curve from 0 to 12 h (AUC0-12) and peak plasma drug concentration (C max) were modestly increased in healthy subjects (geometric mean ratios [GMRs], 1.49 and 1.64, respectively). There was no substantial effect of TDF on raltegravir concentration at 12 h postdose (C 12) in healthy subjects (GMR [TDF plus raltegravir-raltegravir alone], 1.03; 90% confidence interval [CI], 0.73 to 1.45), while a modest increase (GMR, 1.42; 90% CI, 0.89 to 2.28) was seen in HIV-1-infected patients. Raltegravir had no substantial effect on tenofovir pharmacokinetics: C 24, AUC, and C max GMRs were 0.87, 0.90, and 0.77, respectively. Coadministration of raltegravir and TDF does not change the pharmacokinetics of either drug to a clinically meaningful degree. Raltegravir and TDF may be coadministered without dose adjustments.

scholarly journals Herb-Drug Interaction betweenEchinacea purpureaand Darunavir-Ritonavir in HIV-Infected Patients

2010 ◽  
Vol 55 (1) ◽  
pp. 326-330 ◽  
Author(s):  
José Moltó ◽  
Marta Valle ◽  
Cristina Miranda ◽  
Samandhy Cedeño ◽  
Eugenia Negredo ◽  
...  
Keyword(s):  
High Performance ◽  
Geometric Mean ◽  
Echinacea Purpurea ◽  
The Body ◽  
Pharmacokinetic Parameters ◽  
Root Extract ◽  
Open Label ◽  
Fixed Sequence ◽  
Time Curve ◽  
Sequence Study

ABSTRACTThe aim of this open-label, fixed-sequence study was to investigate the potential ofEchinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included.E. purpurearoot extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m2. Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration ofE. purpureawith darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.

A drug-drug interaction (DDI) study to assess the effect of oral galeterone on the pharmacokinetics (PK) of oral midazolam.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 316-316
Author(s):  
Karen J. Ferrante ◽  
Douglas B Jacoby ◽  
Daryl Sonnichsen
Keyword(s):  
Geometric Mean ◽  
Point Estimate ◽  
Open Label ◽  
Fixed Sequence ◽  
Geometric Means ◽  
Fda Guidance ◽  
Point Estimates ◽  
Oral Midazolam ◽  
Androgen Binding

316 Background: Galeterone (gal) is a semisynthetic steroid that targets androgen receptor (AR) signaling via increased AR protein degradation, inhibition of CYP17 activity, and inhibition of androgen binding to AR. Gal is a novel potential treatment for prostate cancer. In vitro, gal competitively inhibits CYP3A4 (IC50 = 5.5 μM; midazolam as substrate). This clinical study evaluated whether multiple daily doses of gal alter the single-dose PK of midazolam, a sensitive probe substrate for functional CYP3A4 intestinal and hepatic activity. Methods: In an open-label, fixed sequence, DDI study, 18 healthy male volunteers received midazolam 2 mg Day 1 and Day 5 and gal 2550 mg Days 2-5. Midazolam plasma PK was determined on Days 1 and 5. The effect of gal on the natural log-transformed Cmax, AUC0-inf, and AUC0-t of midazolam was assessed with a linear mixed-effects model; point estimates for geometric means, geometric mean ratios with 90% confidence intervals were determined. Safety was also monitored. Results: The Tmax of midazolam was not altered by gal coadministration. The < 2-fold increases in midazolam Cmax and AUCs were statistically significant. For Cmax, the point estimate of the geometric least squares (LS) mean ratio between the 2 treatments was 1.25 (90% CI: 1.05, 1.48). Higher ratios were observed for the AUC ratios, with LS mean ratio for AUC0-t of 1.57 (90% CI: 1.43, 1.73) and for AUC0-inf of 1.58 (90% CI: 1.42, 1.75). The mean midazolam t1/2 was approximately 76% higher with gal coadministration. Multiple doses of gal were well tolerated with no apparent effect on the safety of midazolam. Conclusions: Per FDA guidance, < 2-fold increases in midazolam Cmax and AUCs observed with gal coadministration support its classification as a weak inhibitor of CYP3A4. Given the similar or higher in vitro IC50’s for CYP2C8 and CYP2C19, respectively, a comparable or lesser degree of enzyme inhibition is expected for gal 2550 mg daily. Based on these results, concurrent CYP3A4, CYP2C8, and CYP2C19 substrates are not contraindicated in patients taking gal; caution is advised in patients receiving or initiating sensitive CYP3A4, CYP2C8, and CYP2C19 substrates, especially those with a narrow therapeutic range.

scholarly journals Pharmacokinetics of Telbivudine in Healthy Subjects and Absence of Drug Interaction with Lamivudine or Adefovir Dipivoxil

2006 ◽  
Vol 50 (7) ◽  
pp. 2309-2315 ◽  
Author(s):  
Xiao-Jian Zhou ◽  
Barbara A. Fielman ◽  
Deborah M. Lloyd ◽  
George C. Chao ◽  
Nathaniel A. Brown
Keyword(s):  
Single Dose ◽  
Steady State ◽  
Plasma Concentration ◽  
Healthy Subjects ◽  
Adefovir Dipivoxil ◽  
Geometric Mean ◽  
Time Curve ◽  
Concentration Time ◽  
Plasma Pharmacokinetics ◽  
Plasma Concentration Time Curve

ABSTRACT Two phase I studies were conducted to assess the plasma pharmacokinetics of telbivudine and potential drug-drug interactions between telbivudine (200 or 600 mg/day) and lamivudine (100 mg/day) or adefovir dipivoxil (10 mg/day) in healthy subjects. Study drugs were administered orally. The pharmacokinetics of telbivudine were characterized by rapid absorption with biphasic disposition. The maximum concentrations in plasma (C max) were reached at median times ranging from 2.5 to 3.0 h after dosing. Mean single-dose C max and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) were 1.1 and 2.9 μg/ml and 7.4 and 21.8 μg · h/ml for the 200- and 600-mg telbivudine doses, respectively. Steady state was reached after daily dosing for 5 to 7 days. The mean steady-state C max and area under the plasma concentration-time curve over the dosing interval (AUCτ) were 1.2 and 3.4 μg/ml and 8.9 and 27.5 μg · h/ml for the 200- and 600-mg telbivudine repeat doses, respectively. The steady-state AUCτ of telbivudine was 23 to 57% higher than the single-dose values. Concomitant lamivudine or adefovir dipivoxil did not appear to significantly alter the steady-state plasma pharmacokinetics of telbivudine; the geometric mean ratios and associated 90% confidence interval (CI) for the AUCτ of telbivudine alone versus in combination were 106.3% (92.0 to 122.8%) and 98.6% (86.4 to 112.5%) when coadministered with lamivudine and adefovir dipivoxil, respectively. Similarly, the steady-state plasma pharmacokinetics of lamivudine or adefovir were not markedly affected by the coadministration of telbivudine; the geometric mean ratios and associated 90% CI, alone versus in combination with telbivudine, were 99.0% (87.1 to 112.4%) and 92.2% (84.0 to 101.1%), respectively, for the lamivudine and adefovir AUCτ values. Moreover, the combination regimens studied were well tolerated in all subjects. The results from these studies provide pharmacologic support for combination therapy or therapy switching involving telbivudine, lamivudine, and adefovir dipivoxil for the treatment of chronic hepatitis B virus infection.

scholarly journals Pharmacokinetic Interaction between Maraviroc and Fosamprenavir-Ritonavir: an Open-Label, Fixed-Sequence Study in Healthy Subjects

2013 ◽  
Vol 57 (12) ◽  
pp. 6158-6164 ◽  
Author(s):  
Manoli Vourvahis ◽  
Anna Plotka ◽  
Laure Mendes da Costa ◽  
Annie Fang ◽  
Jayvant Heera
Keyword(s):  
Healthy Subjects ◽  
Geometric Mean ◽  
Active Form ◽  
Pharmacokinetic Interaction ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Open Label ◽  
Fixed Sequence ◽  
Dosing Interval ◽  
Period 2

ABSTRACTThis open-label, fixed-sequence, phase 1 study evaluated the pharmacokinetic interaction between maraviroc (MVC) and ritonavir-boosted fosamprenavir (FPV/r) in healthy subjects. In period 1, subjects received 300 mg of MVC twice daily (BID; cohort 1) or once daily (QD; cohort 2) for 5 days. In period 2, cohort 1 subjects received 700/100 mg of FPV/r BID alone on days 1 to 10 and then FPV/r at 700/100 mg BID plus MVC at 300 mg BID on days 11 to 20; cohort 2 subjects received FPV/r at 1,400/100 mg QD alone on days 1 to 10 and then FPV/r at 1,400/100 mg QD plus MVC at 300 mg QD on days 11 to 20. Pharmacokinetic parameters, assessed on day 5 of period 1 and on days 10 and 20 of period 2, included the maximum plasma concentration (Cmax), the concentration at end of dosing interval (Cτ), and the area under the curve over dosing interval (AUCτ). Safety and tolerability were also assessed. MVC geometric mean AUCτ,Cmax, andCτwere increased by 149, 52, and 374%, respectively, after BID dosing with FPV/r, and by 126, 45, and 80%, respectively, after QD dosing. Amprenavir (the active form of the prodrug fosamprenavir) and ritonavir exposures were decreased in the presence of MVC with amprenavir AUCτ,Cmax, andCτdecreased by 34 to 36% in the presence of FPV/r plus maraviroc BID and by 15 to 30% with FPV/r plus MVC QD both compared to FPV/r alone. The overall all-causality adverse-event (AE) incidence rate was 96.4%; all AEs were of mild or moderate severity. Commonly reported treatment-related AEs (>20% of patients overall) included diarrhea, fatigue, abdominal discomfort, headache, and nausea. No serious AEs or deaths occurred. In summary, maraviroc exposure increased in the presence of FPV/r, whereas MVC coadministration decreased amprenavir and ritonavir exposures. MVC dosed at 300 mg BID with FPV/r is not recommended due to concerns of lower amprenavir exposures; however, no dose adjustment is warranted with MVC at 150 mg BID in combination with FPV/r based on the available clinical data. MVC plus FPV/r was generally well tolerated; no new safety signals were detected.

scholarly journals Effects of the Chinese Herbal Formulation (Liu Wei Di Huang Wan) on the Pharmacokinetics of Isoflavones in Postmenopausal Women

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Wirin Limopasmanee ◽  
Sunee Chansakaow ◽  
Noppamas Rojanasthien ◽  
Maleeya Manorot ◽  
Chaichan Sangdee ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Postmenopausal Women ◽  
Pharmacokinetic Parameters ◽  
Soy Milk ◽  
Open Label ◽  
Fixed Sequence ◽  
Time Curve ◽  
Oral Doses

A combination of soy isoflavones andLiu Wei Di Huang Wan(LWDHW) is potentially effective for postmenopausal women with intolerable vasomotor episodes who are not suitable candidates for hormonal therapy. The objective of this open-label, three-phase, crossover study was to determine the influence of both single and multiple oral doses of LWDHW on isoflavone pharmacokinetics in healthy postmenopausal women. Eleven subjects were assigned to receive the following regimens in a fixed sequence with washout periods of at least one week: Phase A, a single oral dose of soy milk; Phase B, a single oral dose of soy milk coadministered with LWDHW; and Phase C, multiple oral doses of LWDHW for 14 days followed by a single oral dose of soy milk. Blood samples were collected and mixed withβ-glucuronidase/sulfatase to hydrolyze isoflavone conjugates to their respective aglycones (i.e., daidzein and genistein) and were determined using high performance liquid chromatography. The pharmacokinetic parameters analyzed were maximal plasma concentrationCmax, time to reach peak concentrationTmax, area under the plasma concentration-time curve (AUC), and half-life (t1/2). The results found no statistically significant differences in pharmacokinetic parameters of daidzein and genistein among the three regimens.

scholarly journals Atogepant and sumatriptan: no clinically relevant drug–drug interactions in a randomized, open-label, crossover trial

2021 ◽  
Author(s):  
Ramesh Boinpally ◽  
Abhijeet Jakate ◽  
Matthew Butler ◽  
Antonia Periclou
Keyword(s):  
Plasma Concentration ◽  
Crossover Trial ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Geometric Mean ◽  
Open Label ◽  
Time Curve ◽  
Concentration Time ◽  
Pharmacokinetic Interactions ◽  
Randomized Crossover Study

Aim: To evaluate pharmacokinetic interactions of atogepant with sumatriptan, an open-label, randomized, crossover study was conducted. Patients & methods: Thirty healthy adults received atogepant 60 mg, sumatriptan 100 mg, or coadministered drugs. Primary end point was geometric mean ratios (GMRs) and 90% CIs of interventions for area under the plasma concentration–time curve from time 0 to t (AUC0-t) or infinity (AUC0-∞) and peak plasma concentration (Cmax). Results: Atogepant GMRs for AUC0-t and AUC0-∞ versus with sumatriptan were within 90% CI 0.80–1.25, indicating no interaction; atogepant Cmax was reduced by 22% (GMR: 0.78; 90% CI: 0.69–0.89) with sumatriptan. Sumatriptan GMRs for AUC0-t, AUC0-∞ and Cmax versus with atogepant were within 90% CI 0.80–1.25. Conclusion: Atogepant with sumatriptan had no clinically relevant pharmacokinetic interactions.

scholarly journals Effects of CYP3A4 and P-glycoprotein inhibition or induction on the pharmacokinetics of ubrogepant in healthy adults: Two phase 1, open-label, fixed-sequence, single-center, crossover trials

2021 ◽  
Vol 4 ◽  
pp. 251581632110373
Author(s):  
Abhijeet Jakate ◽  
Ramesh Boinpally ◽  
Matthew Butler ◽  
Wendy Ankrom ◽  
Marissa F Dockendorf ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Phase 1 ◽  
Geometric Mean ◽  
Healthy Adults ◽  
Single Center ◽  
Open Label ◽  
Two Phase ◽  
Fixed Sequence ◽  
P Glycoprotein ◽  
Crossover Trials

Background: Ubrogepant is metabolized by cytochrome P450 3A4 (CYP3A4) and is a P-glycoprotein (P-gp) substrate. Objective: To assess effects of multiple-dose moderate-strong CYP3A4 and strong P-gp inhibitors and inducers on ubrogepant pharmacokinetic (PK) parameters. Methods: Two phase 1, open-label, fixed-sequence, single-center, crossover trials enrolled healthy adults to receive ubrogepant 20 mg with/without verapamil 240 mg (a moderate CYP3A4 inhibitor) or ketoconazole 400 mg (a strong CYP3A4 and P-gp transporter inhibitor) (Study A), or ubrogepant 100 mg with/without rifampin 600 mg (a strong CYP3A4 inducer and P-gp inducer) (Study B). Outcomes included ubrogepant PK parameters (area under plasma concentration-time curve, time 0 through infinity [AUC0-∞], peak plasma concentration [Cmax]), and safety (treatment-emergent adverse events [TEAEs]). PK parameters were compared between ubrogepant with/without coadministered medications using linear mixed-effects models. Cmax and AUC0-∞ least-squares geometric mean ratios (GMR) of ubrogepant with/without coadministration were constructed. Results: Twelve participants enrolled in Study A and 30 in Study B. AUC0-∞ and Cmax GMR (90% CI) were 3.53 (3.32–3.75) and 2.80 (2.48–3.15), respectively, for ubrogepant with verapamil; 9.65 (7.27–12.81) and 5.32 (4.19–6.76) with ketoconazole; and 0.22 (0.20–0.24) and 0.31 (0.27–0.36) with rifampin. TEAEs were predominantly mild; no treatment-related serious TEAEs or TEAE-related discontinuations occurred. Conclusion: The PK of ubrogepant were significantly affected by the concomitant use of CYP3A4 moderate-strong inhibitors and strong inducers.

scholarly journals No relevant pharmacokinetic drug–drug interaction between nintedanib and pirfenidone

2018 ◽  
Vol 53 (1) ◽  
pp. 1801060 ◽  
Author(s):  
Luca Richeldi ◽  
Sophie Fletcher ◽  
Huzaifa Adamali ◽  
Nazia Chaudhuri ◽  
Sabrina Wiebe ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Plasma Concentration ◽  
Geometric Mean ◽  
Maximum Plasma ◽  
Open Label ◽  
Time Curve ◽  
Drug Drug Interaction ◽  
Group 2 ◽  
Pharmacokinetic Drug ◽  
Group 1

Nintedanib and pirfenidone are approved treatments for idiopathic pulmonary fibrosis (IPF). This open-label, two-group trial investigated the pharmacokinetic drug–drug interaction between these two drugs in patients with IPF.Subjects not treated with antifibrotics at screening (group 1, n=20) received a single nintedanib dose (150 mg) followed by pirfenidone (titrated to 801 mg thrice daily) for 3 weeks, with a further single nintedanib dose (150 mg) on the last day (day 23). Subjects treated with pirfenidone at screening (group 2, n=17) continued to receive pirfenidone alone (801 mg thrice daily) for 7 days, then co-administered with nintedanib (150 mg twice daily) for a further 7 days, before single doses of both treatments on day 16.In group 1, adjusted geometric mean (gMean) ratios (with/without pirfenidone) were 88.6% and 80.6% for nintedanib area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax), respectively. In group 2, gMean ratios (with/without nintedanib) were 97.2% and 99.5% for pirfenidone AUC and Cmax, respectively. For all parameters, the 90% confidence intervals included 100%, suggesting similar exposure for administration alone and when co-administered. Both treatments were well tolerated.These data indicate there is no relevant pharmacokinetic drug–drug interaction between nintedanib and pirfenidone when co-administered in IPF patients.

scholarly journals Effect of Cilostazol on the Pharmacokinetics of Simvastatin in Healthy Subjects

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Jung-Ryul Kim ◽  
Jin Ah Jung ◽  
Seokuee Kim ◽  
Wooseong Huh ◽  
Jong-Lyul Ghim ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Subjects ◽  
Serum Lipid ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Lipid Profiles ◽  
Open Label ◽  
Fixed Sequence ◽  
Simvastatin Acid

Purpose. We evaluated potential drug-drug interactions between cilostazol and simvastatin, both CYP3A substrates, in healthy subjects. Methods. An open-label, two-period, fixed-sequence clinical study was conducted. Seventeen subjects were given a single oral dose of simvastatin 40 mg on day 1 and multiple oral doses of cilostazol 100 mg twice daily on days 2 to 5 followed by a single dose of cilostazol and simvastatin on day 6. Plasma concentrations of simvastatin and its active metabolite, simvastatin acid, were measured using liquid chromatography-tandem mass spectrometry for pharmacokinetic assessment. Moreover, serum lipid profiles under fasting conditions were determined. Results. The geometric mean ratios of the area under the plasma concentration-time curve from time zero to time infinity of simvastatin combined with cilostazol to that of simvastatin alone were 1.64 (90% CI, 1.38-1.95) for simvastatin and 1.31 (1.04-1.66) for simvastatin acid. In addition, coadministration with cilostazol significantly increased the maximum concentration of simvastatin and simvastatin acid, up to 1.8-fold and 1.6-fold, respectively. However, the effects of a single dose of simvastatin on serum lipid profiles were not affected notably when simvastatin was coadministered with cilostazol. Conclusions. Multiple doses of cilostazol increased the systemic exposure of simvastatin and simvastatin acid following a single dose of simvastatin.

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