The effects of ritonavir and lopinavir/ritonavir on the pharmacokinetics of a novel CCR5 antagonist, aplaviroc, in healthy subjects

AIMS: This study assessed the effects of the CYP3A inhibitors lopinavir/ritonavir (LPV/r) on the steady-state pharmacokinetics (PK) of aplaviroc (APL), a CYP3A4 substrate, in healthy subjects. METHODS: In Part 1, APL PK was determined in eight subjects who received a single oral 50-mg APL test dose with/without a single dose of 100 mg ritonavir (RTV). Part 2 was conducted as an open-label, single-sequence, three-period repeat dose study in a cohort of 24 subjects. Subjects received APL 400 mg every 12 h (b.i.d.) for 7 days (Period 1), LPV/r 400/100 mg b.i.d. for 14 days (Period 2) and APL 400 mg + LPV/r 400/100 mg b.i.d. for 7 days (Period 3). All doses were administered with a moderate fat meal. PK sampling occurred on day 7 of Periods 1 and 3 and day 14 of Period 2. RESULTS: In Part 1, a single RTV dose increased the APL AUC(0-infinity) by 2.1-fold [90% confidence interval (CI) 1.9, 2.4]. Repeat dose coadministration of APL with LPV/r increased APL exposures to a greater extent with the geometric least squares mean ratios (90% CI) being 7.7 (6.4, 9.3), 6.2 (4.8, 8.1) and 7.1 (5.6, 9.0) for the APL AUC, C(max), and C(min), respectively. No change in LPV AUC or C(max) and a small increase in RTV AUC and C(max) (28% and 32%) were observed. The combination of APL and LPV/r was well tolerated and adverse events were mild in severity with self-limiting gastrointestinal complaints most commonly reported. CONCLUSIONS: Coadministration of APL and LPV/r was well tolerated and resulted in significantly increased APL plasma concentrations.     

Model-based approach to dose optimization of lopinavir/ritonavir when co-administered with rifampicin

AIMS

Rifampicin, a key component of antitubercular treatment, profoundly reduces lopinavir concentrations. The aim of this study was to develop an integrated population pharmacokinetic model accounting for the drug–drug interactions between lopinavir, ritonavir and rifampicin, and to evaluate optimal doses of lopinavir/ritonavir when co-administered with rifampicin.

METHODS

Steady-state pharmacokinetics of lopinavir and ritonavir were sequentially evaluated after the introduction of rifampicin and gradually escalating the dose in a cohort of 21 HIV-infected adults. Intensive pharmacokinetic sampling was performed after each dose adjustment following a morning dose administered after fasting overnight. A population pharmacokinetic analysis was conducted using NONMEM 7.

RESULTS

A simultaneous integrated model was built. Rifampicin reduced the oral bioavailability of lopinavir and ritonavir by 20% and 45% respectively, and it increased their clearance by 71% and 36% respectively. With increasing concentrations of ritonavir, clearance of lopinavir decreased in an E_max relationship. Bioavailability was 42% and 45% higher for evening doses compared with morning doses for lopinavir and ritonavir, respectively, while oral clearance of both drugs was 33% lower overnight. Simulations predicted that 99.5% of our patients receiving doubled doses of lopinavir/ritonavir achieve morning trough concentrations of lopinavir > 1 mg l⁻¹ during rifampicin co-administration, and 95% of those weighing less than 50 kg achieve this target already with 600/150 mg doses of lopinavir/ritonavir.

CONCLUSIONS

The model describes the drug–drug interactions between lopinavir, ritonavir and rifampicin in adults. The higher trough concentrations observed in the morning were explained by both higher bioavailability with the evening meal and lower clearance overnight.     

Artemether-lumefantrine co-administration with antiretrovirals: population pharmacokinetics and dosing implications

AIM

Drug–drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug–drug interactions between the antimalarial drugs, lumefantrine, artemether and their respective metabolites desbutyl-lumefantrine and dihydroartemisinin, and the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir.

METHOD

Data from two clinical studies, investigating the influence of the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir on the pharmacokinetics of the antimalarial drugs lumefantrine, artemether and their respective metabolites, in HIV infected patients were pooled and analyzed using a non-linear mixed effects modelling approach.

RESULTS

Efavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 69.9% and 25.2%, respectively) while lopinavir/ritonavir substantially increased the exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether-lumefantrine dose is required to achieve equivalent exposures when co-administered with efavirenz (250% increase) and nevirapine (75% increase). When co-administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required.

CONCLUSION

There are substantial drug interactions between artemether-lumefantrine and efavirenz, nevirapine and ritonavir/lopinavir. Given the readily saturable absorption of lumefantrine, the dose adjustments predicted to be necessary will need to be evaluated prospectively in malaria-HIV co-infected patients.     

Lopinavir/ritonavir population pharmacokinetics in neonates and infants

AIMS

Because of immature hepatic metabolism, lopinavir could present specific pharmacokinetics in the first weeks of life. We aimed at determining the optimal dosing regimen in neonates and infants weighing 1 to 10.5 kg.

METHODS

Lopinavir/ritonavir (LPV/r) pharmacokinetics were studied in 96 infants using a population approach.

RESULTS

A one-compartment model described LPV/r pharmacokinetics. Normalized to a 70 kg adult using allometry, clearance (CL/F) and distribution volume (V/F) estimates were 5.87 l h⁻¹ 70 kg⁻¹ and 91.7 l 70 kg⁻¹. The relative bioavailabilty, F, increased with post-menstrual age (PMA) and reached 50% of the adult value at 39.7 weeks.

CONCLUSIONS

Size and PMA explained some CL/F and V/F variability in neonates/infants. Based upon trough concentration limitations, suggested LPV/r dosing regimens were 40 mg 12 h⁻¹, 80 mg 12 h⁻¹ and 120 mg 12 h⁻¹ in the 1–2 kg, 2–6 kg and 6–10 kg group, respectively.     

Absence of circadian variation in the pharmacokinetics of lopinavir/ritonavir given as a once daily dosing regimen in HIV-1-infected patients

AIMS: To compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily in the morning compared with the evening. METHODS: This was a randomized, two-way, cross-over study in HIV+ subjects. In each subject the pharmacokinetics of each drug were characterized after 2 weeks of LPV/r 800/200 mg administered once daily at 08.00 h and 19.00 h. On study days, LPV/r was taken with a standardized meal (800 kCal, 25% from fat) after fasting for at least 5 h. LPV/r concentrations were measured by LC-MS/MS, and the data were analyzed by noncompartmental pharmacokinetic analysis. RESULTS: Fourteen subjects completed the study (all men, mean age/weight 44 year/81 kg). The median (interquartile range) LPV AUC(0,24 h), maximum plasma concentration (C(max)) and concentration at the end of the dosing interval (C(24 h)) after am and pm dosing was, respectively, 143 (116-214) mg l(-1) h, 12.8 (10.3-17.2) mg l(-1), 1.34 (0.58-3.25) mg l(-1), and 171 (120-232) mg l(-1) h, 12.9 (8.22-16.3) mg l(-1), 1.15 (0.59-1.98) mg l(-1). The geometric mean ratio (GMR, am : pm) and 95% CI of the LPV AUC(0,24 h), C(max), and C(24 h) was 0.91 (0.79, 1.06), 1.11 (0.94, 1.32), and 1.19 (0.72, 1.96), respectively. The median ritonavir C(max) after am and pm dosing was 1.05 and 0.90 mg l(-1), respectively. The GMR (95% CI) of the RTV AUC(0,24 h), C(max), and C(24 h) was 0.93 (0.80, 1.08), 1.27 (1.00, 1.63), and 1.04 (0.68, 1.60), respectively. Administration of LPV/r in a once-daily regimen was generally well tolerated. CONCLUSIONS: No differences were observed in the pharmacokinetics of LPV/r after am or pm dosing with food, which suggests that this once daily combination, can be taken in the morning or evening. Such flexibility in dosing may improve adherence.     

Effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam

AIMS

The aim of the study was to determine the effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam in the plasma.

METHODS

We conducted a randomized, open-label, four-way crossover study in 10 healthy volunteers. Each volunteer received oral midazolam 2 mg or intravenous midazolam 0.025 mg kg⁻¹ with and without oral clotrimazole troches 10 mg taken three times daily for 5 days. Each study period was separated by 14 days. Serial blood samples were collected up to 24 h after oral midazolam and 6 h after intravenous midazolam. Plasma concentrations for midazolam and its metabolite 1-hydroxymidazolam were measured and fitted to a noncompartmental model to estimate the pharmacokinetic parameters.

RESULTS

Ten healthy volunteers aged 21–26 years provided written informed consent and were enrolled into the study. Clotrimazole decreased the apparent oral clearance of midazolam from 57 ± 13 l h⁻¹[95% confidence interval 48, 66] to 36 ± 9.8 l h⁻¹ (95% confidence interval 29, 43) (P= 0.003). These changes were accompanied by a decrease in the area under the concentration–time curve (mean difference 22 µg h⁻¹ l⁻¹, P= 0.001) and bioavailability (mean difference 0.21, P= NS). There were no significant differences in the systemic clearance of midazolam with or without clotrimazole troches.

CONCLUSIONS

Oral clotrimazole troches decreased the apparent oral clearance of midazolam; no significant differences in the systemic clearance of midazolam were found.     

洛匹那韦/利托那韦临床应用概述

洛匹那韦/利托那韦是复方制剂,洛匹那韦与病毒蛋白酶催化部位结合干扰病毒装配过程,低剂量利托那韦抑制人体CYP3A介导洛匹那韦代谢,提高生物利用度,提高血浆中洛匹那韦药物浓度。本文对洛匹那韦/利托那韦在病毒感染性疾病的临床应用、不良反应、药物相互作用等进行介绍。     

The effect of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of cilostazol and its active metabolites in healthy Korean subjects

AIMS

The primary objective of this study was to evaluate the effects of Ginkgo biloba extracts (GBE) on the pharmacokinetics of cilostazol and its metabolites. The secondary objective was to assess the effect of GBE on the pharmacodynamics of cilostazol.

METHODS

A randomized, double-blind, two-way crossover study was conducted with 34 healthy Korean subjects. All subjects were given an oral dose of cilostazol (100 mg) plus GBE (80 mg) or cilostazol (100 mg) plus placebo twice daily for 7 days. Plasma concentrations of cilostazol and its active metabolites (3,4-dehydrocilostazol and 4′-trans-hydroxycilostazol) were measured using liquid chromatography–tandem mass spectroscopy on day 7 for pharmacokinetic assessment. The adenosine diphosphate-induced platelet aggregation and bleeding time were measured at baseline and on day 7 for pharmacodynamic assessment.

RESULTS

The geometric mean ratios of area under the concentration–time curve for dosing interval for cilostazol plus GBE vs. cilostazol plus placebo were 0.96 (90% confidence interval, 0.89–1.03; P = 0.20) for cilostazol, 0.96 (90% confidence interval, 0.90–1.02; P = 0.30) for 3,4-dehydrocilostazol and 0.98 (90% confidence interval, 0.93–1.03; P = 0.47) for 4′-trans-hydroxycilostazol. The change of aggregation after administration of cilostazol plus GBE seemed to be 1.31 times higher compared with cilostazol plus placebo, without statistical significance (P = 0.20). There were no significant changes in bleeding times and adverse drug reactions between the treatments.

CONCLUSIONS

Co-administration of GBE showed no statistically significant effects on the pharmacokinetics of cilostazol in healthy subjects. A large cohort study with long-term follow-up may be needed to evaluate the possible pharmacodynamic interaction between cilostazol and GBE, given that there was a remarkable, but not statistically significant, increase in inhibition of platelet aggregation.     

Pharmacokinetics of the selective prostacyclin receptor agonist selexipag in rats,dogs and monkeys

1.?This study examined the pharmacokinetics, distribution, metabolism and excretion of the selective prostacyclin receptor agonist selexipag (NS-304; ACT-293987) and its active metabolite MRE-269 (ACT-33679). The compounds were investigated following oral and/or intravenous administration to intact rats, dogs and monkeys, and bile-duct-cannulated rats and dogs.

2.?After oral administration of [¹⁴C]selexipag, selexipag was well absorbed in rats and dogs with total recoveries of over 90% of the dose, mainly in the faeces. Biliary excretion was the major elimination pathway for [¹⁴C]MRE-269 as well as [¹⁴C]selexipag, while renal elimination was of little importance. [¹⁴C]Selexipag-related radioactivity was secreted into the milk in lactating rats.

3.?Plasma was analysed for total radioactivity, selexipag and MRE-269 in rats and monkeys. Selexipag was negligible in rat plasma due to extensive metabolism, and MRE-269 was present in rat and monkey plasma. A species difference was clearly evident when selexipag was incubated in rat, dog and monkey plasma.

4.?Total radioactivity was rapidly distributed to tissues. The highest concentrations were found in the bile duct and liver without significant accumulation or persistence, while there was limited melanin-associated binding, penetration of the blood–brain barrier and placental transfer of drug-related materials.     

Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers

Aims To assess the effects of the protease inhibitor ritonavir on the pharmacokinetics of ethinyl oestradiol in  healthy female volunteers.
Methods This was an open-label, single centre study in 23 subjects who received two single doses of oral contraceptive containing 50  μg ethinyl oestradiol on Day 1 (alone) and on Day 29 during concomitant ritonavir. Each subject received 16  days of every 12  h doses of ritonavir from Day 15 through Day 30. Blood samples were collected for serum ethinyl oestradiol concentrations for 48  h after each dose and for plasma ritonavir on Day 29 at 0 and 4  h postdose.
Results Statistically significant decreases in ethinyl oestradiol mean C _max (−32%) and mean AUC (−41%), and a statistically significant increase in the mean terminal elimination rate constant (+31%) were observed during concomitant ritonavir. The harmonic mean terminal half-life decreased from 17  h to 13  h during concomitant ritonavir. No statistically significant change was noted in t _max. The ratios of means (95% confidence intervals) for C _max and AUC were 0.682 (0.612–0.758) and 0.595 (0.506–0.694), respectively. The changes in ethinyl oestradiol pharmacokinetics were consistent with an increase in clearance from enzymatic induction of glucuronidation and/or cytochrome P450  hydroxylation. Mean steady-state ritonavir concentrations of 6.5 and 13.4  μg  ml⁻¹ were observed at 0 and 4  h postdose, respectively.
Conclusions Considering the extent of the decrease in ethinyl oestradiol concentrations, the use of alternate contraceptive measures should be considered when ritonavir is being administered.     

Effects of ketoconazole treatment on the pharmacokinetics of safinamide and its plasma metabolites in healthy adult subjects

The purpose of this mechanistic drug interaction study was to investigate the effects of ketoconazole on the pharmacokinetics of safinamide. Ketoconazole was applied as a potent prototypic inhibitor of cytochrome CYP3A4, to determine the role of CYP3A4 in the metabolic clearance of safinamide. In an open‐label, randomized, two‐period, two‐sequence cross‐over study, 14 healthy adult subjects (7 males/7 females) received two single doses of 100 mg safinamide: alone and on top of multiple doses of ketoconazole (200 mg b.i.d.) given over 6 days. Serial blood samples were collected over 240 h post dose to quantify safinamide parent drug and metabolite concentrations for pharmacokinetic evaluation. Safinamide exposure was essentially unchanged when administered with and without ketoconazole: C_max and AUC_0‐∞ point estimates (90% CIs) for the treatment comparison were 106.6 (101.0; 112.4) and 112.9 (109.8; 116.03), respectively. Similarly, ketoconazole did not influence the formation and clearance of safinamide metabolites to a clinically relevant extent. Overall, the study shows that CYP3A4 plays a minor role in the metabolism of safinamide in vivo. Therefore, safinamide can be administered together with potent CYP3A4 inhibitors without any requirement for dose adjustment. Copyright © 2012 John Wiley & Sons, Ltd.     

LC-MS/MS法同时测定洛匹那韦和利托那韦的血浆浓度

建立液相色谱-串联质谱法 (LC-MS/MS) 测定人血浆中洛匹那韦 (LPV)、利托那韦 (RTV) 的浓度。血浆样品经碱化沉淀蛋白后, 经乙酸乙酯液-液萃取, 以甲醇-0.1%甲酸水溶液 (80∶20) 为流动相, Agilent ZORBAX Eclipse XDB-C₁₈ (150 mm × 4.6 mm ID, 5 μm) 柱分离; 采用电喷雾电离源, 以多反应监测 (MRM) 方式进行正离子检测, 用于定量分析的离子对LPV为629.6→155.2, RTV为721.4→268.2, 内标替米沙坦 (TEL) 为515.2→276.2。测定血浆中LPV线性范围为62.5～10 000 ng·mL⁻¹, 检测限为15 pg·mL⁻¹, RTV的线性范围为12.5～2 000 ng·mL⁻¹, 检测限为8 pg·mL⁻¹, r均大于0.99。日内和日间精密度均小于15%, 提取回收率均大于75%。该法选择性强、灵敏度高、重现性好, 能同时快速、准确测定人血浆LPV和RTV浓度, 为临床治疗药物浓度监测 (TDM) 奠定基础。     

Model-based evaluation of the pharmacokinetic differences between adults and children for lopinavir and ritonavir in combination with rifampicin

Aims

Rifampicin profoundly reduces lopinavir concentrations. Doubled doses of lopinavir/ritonavir compensate for the effect of rifampicin in adults, but fail to provide adequate lopinavir concentrations in young children on rifampicin-based antituberculosis therapy. The objective of this study was to develop a population pharmacokinetic model describing the pharmacokinetic differences of lopinavir and ritonavir, with and without rifampicin, between children and adults.

Methods

An integrated population pharmacokinetic model developed in nonmem 7 was used to describe the pharmacokinetics of lopinavir and ritonavir in 21 HIV infected adults, 39 HIV infected children and 35 HIV infected children with tuberculosis, who were established on lopinavir/ritonavir-based antiretroviral therapy with and without rifampicin-containing antituberculosis therapy.

Results

The bioavailability of lopinavir was reduced by 25% in adults whereas children on antituberculosis treatment experienced a 59% reduction, an effect that was moderated by the dose of ritonavir. Conversely, rifampicin increased oral clearance of both lopinavir and ritonavir to a lesser extent in children than in adults. Rifampicin therapy in administered doses increased CL of lopinavir by 58% in adults and 48% in children, and CL of ritonavir by 34% and 22% for adults and children, respectively. In children, the absorption half-life of lopinavir and the mean transit time of ritonavir were lengthened, compared with those in adults.

Conclusions

The model characterized important differences between adults and children in the effect of rifampicin on the pharmacokinetics of lopinavir and ritonavir. As adult studies cannot reliably predict their magnitude in children, drug–drug interactions should be evaluated in paediatric patient populations.     

洛匹那韦/利托那韦的不良反应及其机制研究进展

洛匹那韦/利托那韦主要用于人类免疫缺陷（艾滋病）病毒感染的治疗,临床上超说明书用于新型冠状病毒感染的治疗。临床发现使用该药后易引发多种不良反应,主要包括胃肠道反应、肝损伤、代谢紊乱、心血管和神经毒性不良反应。洛匹那韦/利托那韦不良反应机制可能与内质网应激、氧化应激、线粒体应激、细胞凋亡等有关,具有剂量相关性,剂量越高则不良反应越大,主要由肝脏CYP3A代谢,当其与某些具有较强CYP3A4抑制作用的药物共同使用时,往往会加重其不良反应。综述了洛匹那韦/利托那韦片的不良反应及其发生机制,为临床安全、合理用药提供参考。     

Evaluation of pharmacokinetic interactions between long-acting HIV-1 fusion inhibitor albuvirtide and lopinavir/ritonavir,in HIV-infected subjects,combined with clinical study and simulation results

1.?A clinical study to assess the interactions between albuvirtide (320?mg) and lopinavir/ritonavir (400/100?mg) was conducted in 10 HIV-1-infected subjects. Because albuvirtide requires a long period to achieve steady state, and extended monotherapy may lead to early resistance, it is unethical to take albuvirtide alone to achieve steady state. Therefore, a population pharmacokinetic model was developed to predict steady-state concentration-time curve of solely administered albuvirtide.

2.?When albuvirtide and lopinavir/ritonavir were co-administered, the plasma concentration of albuvirtide when the infusion ended (C_end) increased by about 34%, but the geometric mean ratios and 90% confidence intervals (90% CIs) of AUC_(0–t) [1.09 (0.96–1.24)] and C_trough [1.00 (0.83–1.20)] were within the range of 0.8–1.25. For lopinavir, the ratios (90% CIs) of AUC_(0–t), C_max and C_trough were 0.63 (0.49–0.82), 0.67 (0.53–0.86) and 0.65 (0.46–0.91); for ritonavir, those ratios (90% CIs) were 0.62 (0.42–0.91), 0.61 (0.38–0.99) and 0.72 (0.40–1.26), respectively.

3.?Co-administration of albuvirtide with lopinavir/ritonavir has little effect on albuvirtide exposure, but it decreases the plasma exposures of lopinavir/ritonavir. However, the drug–drug interactions may not reduce the effectiveness of this co-therapy, the trough concentration of lopinavir may be sufficient and this combination could achieve similar clinical efficacy with marketed drugs. So, a phase 3 clinical trial without dose adjustment is underway to validate their effectiveness and safety.     

超说明书应用洛匹那韦/利托那韦治疗新型冠状病毒肺炎的临床药学指引

自2019年12月以来，新型冠状病毒肺炎（COVID-19）疫情在全球多个国家和地区出现，目前还没有高质量临床实验证实任何药物可以有效治疗该疾病。洛匹那韦/利托那韦（LPV/r）是中国卫健委发布的试行诊疗方案中推荐试用的抗病毒药物之一。但因证据有限，临床工作者在实践中面临着许多问题，比如缺乏LPV/r在一般和特殊人群中的详细用药指导，诊疗方案中推荐方案的依据和理由不明确等。本文总结和分析了LPV/r在SARS和MERS患者中使用的临床证据，根据现有的安全性数据推荐了在成人和特殊人群中的用药方案，并讨论了治疗时长、注意事项和LPV/r的药学监护策略等。本文目的是解读在COVID-19的治疗中使用LPV/r的理论依据和潜在益处，并指导临床工作者在试用LPV/r治疗COVID-19时合理地使用LPV/r。     

40例新型冠状病毒肺炎患者使用洛匹那韦/利托那韦安全性分析

目的：了解洛匹那韦/利托那韦用于新型冠状病毒（SARS-CoV-2）感染患者的安全性，为新型冠状病毒肺炎（COVID-19）的临床治疗提供建议。方法：对40例新型冠状病毒病确诊患者使用洛匹那韦/利托那韦片后发生药物不良反应的类型、性质、转归等进行统计分析。结果 40例患者中29例（72.5%）发生与洛匹那韦/利托那韦相关不良反应，出现2种及2种以上不良反应13例（32.5%），严重不良反应4例（10%）。不良反应类型主要有甘油三酯升高20例（50%）、恶心7例（17.5%）、腹泻7例（17.5%）等。男女组和不同年龄组间不良反应发生率无统计学差异。结论：洛匹那韦/利托那韦不良反应发生率高，严重不良反应发生率低，可在密切观察患者症状和检验指标的前提下，用于新型冠状病毒肺炎患者。     

Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban,an oral direct factor Xa inhibitor

Aim

Apixaban is an orally active inhibitor of coagulation factor Xa and is eliminated by multiple pathways, including renal and non-renal elimination. Non-renal elimination pathways consist of metabolism by cytochrome P450 (CYP) enzymes, primarily CYP3A4, as well as direct intestinal excretion. Two single sequence studies evaluated the effect of ketoconazole (a strong dual inhibitor of CYP3A4 and P-glycoprotein [P-gp]) and diltiazem (a moderate CYP3A4 inhibitor and a P-gp inhibitor) on apixaban pharmacokinetics in healthy subjects.

Method

In the ketoconazole study, 18 subjects received apixaban 10 mg on days 1 and 7, and ketoconazole 400 mg once daily on days 4–9. In the diltiazem study, 18 subjects received apixaban 10 mg on days 1 and 11 and diltiazem 360 mg once daily on days 4–13.

Results

Apixaban maximum plasma concentration and area under the plasma concentration–time curve extrapolated to infinity increased by 62% (90% confidence interval [CI], 47, 78%) and 99% (90% CI, 81, 118%), respectively, with co-administration of ketoconazole, and by 31% (90% CI, 16, 49%) and 40% (90% CI, 23, 59%), respectively, with diltiazem.

Conclusion

A 2-fold and 1.4-fold increase in apixaban exposure was observed with co-administration of ketoconazole and diltiazem, respectively.