Influence of CYP3A4 Induction/Inhibition on the Pharmacokinetics of Vilazodone in Healthy Subjects

PurposeVilazodone is a serotonin reuptake inhibitor and 5-HT_1A partial agonist approved for the treatment of major depressive disorder in adults. Vilazodone seems to be metabolized primarily by the cytochrome P-450 (CYP) 3A4 isozyme and non-CYP–mediated pathways; concomitant use of drugs that affect CYP3A4 activity could potentially alter systemic exposure to vilazodone. The present studies evaluated whether CYP3A4 inhibition (study 1) or induction (study 2) affected the pharmacokinetics of vilazodone.MethodsParticipants were healthy adult volunteers. Study 1 was conducted in 2 parts and evaluated the pharmacokinetics of single-dose vilazodone administered with multiple-dose (200 mg once daily) ketoconazole, a CYP3A4 inhibitor. Part 1 was an open-label pharmacokinetic assessment of a single 5-mg vilazodone dose with or without ketoconazole. Part 2 was a randomized, double-blind, placebo-controlled, crossover study comparing vilazodone pharmacokinetics after a single 10-mg dose alone or co-administered with ketoconazole or placebo. Study 2 was an open-label, multiple-dose, single-sequence study evaluating the effect of steady-state carbamazepine, a CYP3A4 substrate and inducer, on the pharmacokinetics of steady-state vilazodone (40 mg once daily). Primary pharmacokinetic parameters for both studies were AUC and C_max for vilazodone. Lack of pharmacokinetic interaction was concluded if the 90% CIs of the ratio of vilazodone plus the CYP3A4 inhibitor/inducer relative to vilazodone alone (or plus placebo) for AUC and C_max were within the 80% to 125% range. Subject-reported and investigator-identified adverse events (AEs), laboratory values, vital signs, and 12-lead ECG parameters were recorded.FindingsIn study 1/parts 1 and 2 (n = 15 and 22 enrolled, respectively), mean vilazodone AUC increased 42% and 51%, respectively, in the presence of ketoconazole (expected to be at steady state) versus vilazodone alone (part 1) or with placebo (part 2). The upper limit of the 90% CIs for the vilazodone AUC and C_max geometric mean ratios exceeded 125%. In study 2 (n = 30 enrolled), co-administration of vilazodone and the carbamazepine extended-release formulation decreased mean steady-state vilazodone exposure ~45%, and the 90% CIs for the vilazodone AUC and C_max geometric mean ratios were not within the range of 80% to 125%. In both studies, most AEs were of mild intensity, and gastrointestinal AEs predominated.ImplicationsThese results suggest that up to a 50% decrease of vilazodone dosage should be considered when it is given in combination with strong CYP3A4 inhibitors; conversely, increasing the vilazodone dosage up to a maximum of 80 mg/d should be considered when it is given in combination with strong CYP3A4 inducers. (Study registration numbers: SB-659746/029; VLZ-PK-02.)     

Effect of Ketoconazole on the Pharmacokinetics of the Dipeptidyl Peptidase-4 Inhibitor Teneligliptin: An Open-Label Study in Healthy White Subjects in Germany

Objective

The aim of this study was to examine the effect of ketoconazole, a potent cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) inhibitor, on teneligliptin pharmacokinetics and to evaluate the safety of combined administration of teneligliptin with ketoconazole.

Methods

This open-label, fixed-sequence study was conducted in 16 healthy adult volunteers in Germany. On day 1, under fasting conditions, 20 mg of teneligliptin was administered to evaluate the pharmacokinetics of teneligliptin alone. For 3 days (days 8–10), 400 mg of ketoconazole was administered once daily. On day 11, teneligliptin 20 mg and ketoconazole 400 mg were concurrently administered, and for 2 days (days 12 and 13), ketoconazole was administered once daily. The pharmacokinetic parameters (C_max, T_max, AUC, terminal t_½, apparent total plasma clearance, and V_d during the terminal phase) of teneligliptin on days 1 and 11 were calculated. The safety profile was evaluated based on adverse events and clinical findings. To investigate the role of human P-gp in membrane permeation of teneligliptin, an in vitro study was performed to measure the transcellular transport of teneligliptin across monolayers of human P-gp-expressing cells and control cells.

Results

For C_max and AUC, the geometric least squares mean ratios (90% CIs) of teneligliptin with ketoconazole to teneligliptin alone were 1.37 (1.25–1.50) and 1.49 (1.39–1.60), respectively. There was no change in t_½ of the terminal elimination phase. In addition, the tolerability of teneligliptin coadministered with ketoconazole was acceptable. The in vitro study revealed corrected efflux ratios for teneligliptin of 6.81 and 5.27 at teneligliptin concentrations of 1 and 10 μM, respectively.

Conclusions

Because the exposure to teneligliptin in combined administration with ketoconazole, a potent CYP3A4 and P-gp inhibitor, was less than twice that of administration of teneligliptin alone, it is suggested that combined administration of teneligliptin with drugs and foods that inhibit CYP3A4 should not cause a marked increase in exposure. The results of our in vitro study suggest that teneligliptin is a substrate of P-gp. Clinical Trial Registration: EudraCT No. 2009-016652-51.     

The Effect of Ticagrelor on the Metabolism of Midazolam in Healthy Volunteers

Background

In vitro studies have demonstrated that ticagrelor, an oral antiplatelet agent, is a substrate, activator, and inhibitor of cytochrome P450 (CYP) 3A. Thus, potential CYP3A-mediated drug–drug interactions may occur.

Objectives

The goal of this article was to report study results on the effect of ticagrelor on the pharmacokinetics of oral midazolam (oral midazolam study) and oral versus intravenous (IV) midazolam (oral/IV midazolam study). Secondary objectives included assessing the effect of midazolam on ticagrelor pharmacokinetic parameters, and the safety and tolerability of ticagrelor/midazolam coadministration.

Methods

Two randomized crossover studies were conducted in healthy volunteers (n = 28 in each) with ticagrelor and midazolam. In the first study, volunteers received oral ticagrelor (400 mg daily) or placebo for 6 days, then oral midazolam (7.5 mg). The second study regimen was a single dose of ticagrelor 270 mg, then ticagrelor 180 mg BID for 6 days with a single oral (7.5 mg) or IV (2.5 mg) dose of midazolam.

Results

After oral midazolam administration, ticagrelor significantly reduced the AUC_0–∞ of midazolam (30%–32%) and 4-hydroxymidazolam (42%–47%) but not 1-hydroxymidazolam. After administration of IV midazolam, ticagrelor reduced the AUC_0–∞ of midazolam (12%) and 4-hydroxymidazolam (23%) but not 1-hydroxymidazolam.

Conclusions

These results indicate that ticagrelor can weakly activate the metabolism of midazolam to its major 1′-hydroxy metabolite, and at the same time, seems to weakly inhibit midazolam 4′-hydroxylation. Furthermore, ticagrelor affects both hepatic and intestinal CYP3A activity.     

Effects of Ketoconazole on the Pharmacokinetic Properties of CG100649, A Novel NSAID: A Randomized,Open-Label Crossover Study in Healthy Korean Male Volunteers

Background

CG100649, a novel selective cyclooxygenase-2 inhibitor that also inhibits carbonic anhydrase I/II, is expected to reduce the cardiovascular risk typical of other NSAIDs. Concurrent medications may influence the activities of the cytochrome P450 (CYP) 3A enzyme through which CG100649 is metabolized.

Objectives

This study was designed to evaluate the influence of ketoconazole, a known strong inhibitor of CYP3A, on the pharmacokinetic properties of CG100649.

Methods

This randomized, open-label, 2 × 2 crossover study was conducted in healthy Korean male volunteers. Each subject received the following 2 treatments in a randomly allocated sequence, separated by a washout period of 42 days: single oral dose of CG100649 6 mg, and concurrent dosing of CG100649 6 mg and ketoconazole 400 mg followed by ketoconazole 400 mg/d over 4 days. Blood samples for pharmacokinetic analysis were collected at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 240, 384, and 480 hours after dosing of CG100649 in each sequence. Tolerability assessments were performed throughout the study.

Results

Thirty subjects participated, and 26 subjects completed the study. Seventeen adverse events (AEs) were reported in 10 subjects, and all AEs were recovered without any sequelae. No serious AEs were reported. Six subjects receiving the single dose of CG100649 had 9 AEs, and 7 subjects receiving the combination of ketoconazole and CG100649 had 8 AEs. The C_max of CG100649 with CG100649 only and with concurrent administration of CG100649 + ketoconazole were similar (10.7 and 11.0 ng/mL, respectively). The CG100649 AUC_last with concurrent ketoconazole was 1.29-fold greater than that with CG100649 only (2074.0 and 2685.8 ng · h/mL) and demonstrated a statistically significant difference (P < 0.05). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or AEs between treatments.

Conclusion

Although the AUC of CG100649 increased by 29% with the concurrent medication of ketoconazole, it is considered that concurrent administration of CG100649 with ketoconazole would not change the safety profile of CG100649. ClinicalTrials.gov identifier: NCT01154764.     

Pharmacokinetic interaction between ketoconazole and praziquantel in healthy volunteers

BACKGROUND: Praziquantel, a broad-spectrum anthelminthic, has been reported to undergo extensive first-pass metabolism by cytochrome P450 (CYP) enzymes in vivo. Ketoconazole, a potent CYP3A4 inhibitor, is known to markedly increase plasma concentrations of many co-administered drugs. However, no data are available on the potential pharmacokinetic drug interaction between ketoconazole and praziquantel in humans. OBJECTIVE: To investigate the potential pharmacokinetic interaction of ketoconazole with praziquantel in healthy adult Thai male volunteers. METHODS: In an open-label, randomized two-phase crossover study, separated by a 2-week period, 10 healthy adult Thai male volunteers ingested a single dose of 20 mg/kg praziquantel alone or with co-administration of 400-mg ketoconazole orally daily for 5 days. Venous blood samples were collected at specific times for a 24-h period. Plasma concentrations of praziquantel were determined using high-performance liquid chromatography. A non-compartmental model was applied for pharmacokinetic parameter analysis of praziquantel. RESULTS: Concurrent administration of ketoconazole with praziquantel significantly increased the mean area under the curve from time zero to infinity (AUC(0-alpha)) and maximum plasma concentration (Cmax) of praziquantel by 93% (955.94 +/- 307.74 vs. 1843.10 +/- 336.39 ng h/mL; P < 0.01) and 102% (183.38 +/- 43.90 vs. 371.31 +/- 44.63 ng/mL; P < 0.01), respectively, whereas the mean total clearance (Cl/F) of praziquantel was significantly decreased by 58% (2.65 +/- 0.64 vs. 1.11 +/- 0.35 mL/h/kg; P < 0.01). CONCLUSION: Ketoconazole co-administration alters the pharmacokinetics of praziquantel in humans, possibly through inhibition of CYP3A, particularly CYP3A4, first-pass metabolism of praziquantel. Our data suggest that when praziquantel is co-administered with ketoconazole, the dose of praziquantel could be reduced to half the standard dose of praziquantel to reduce the cost of therapy.     

The effect of single-dose tramadol on oxycodone clearance

We have noticed increased prescribing of tramadol by emergency physicians for breakthrough pain in patients chronically taking oxycodone. Both oxycodone and tramadol undergo oxidative metabolism by CYP2D6 and CYP3A4, suggesting the possibility that tramadol may compete with oxycodone for metabolism. A randomized controlled trial in 10 human volunteers was performed to determine if single-dose tramadol therapy would impair oxycodone clearance. Subjects were randomized whether to enter the control or experimental arm of the study first, with each subject serving as his or her own control. In the control arm, each subject received 10 mg immediate-release oxycodone orally and had serial plasma oxycodone and oxymorphone concentrations measured over 8 h. The experimental arm was identical except that 100 mg tramadol was ingested 1.5 h before oxycodone. Clearance divided by fraction absorbed (CL/f) was calculated using the dose and the area under the 8-h time-plasma oxycodone concentration curve. Peak plasma oxycodone concentrations (C_max) and time until peak oxycodone concentrations (T_max) were secondary outcome parameters. Group size was chosen to produce a power of 0.8 to detect a 20% difference in CL/f between study arms. Values for CL/f, C_max, and T_max were compared between study arms using two-tailed, paired t-tests. No statistically significant difference between groups was demonstrated for any parameter. We failed to demonstrate that single doses of tramadol impaired oxycodone clearance.     

Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers

BACKGROUND: Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co-administered drugs including quinine. OBJECTIVE: To assess the effect of ketoconazole on plasma concentrations of mefloquine in healthy Thai male volunteers. METHODS: In an open, randomized two-phase crossover study separated by a 1-month period, eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone or co-administration with 400 mg/day ketoconazole orally for 10 days. Serial blood samples were collected at specific time points for a 56-day period. Plasma mefloquine and mefloquine carboxylic metabolite concentrations during 56 days were measured by a modified and validated high-performance liquid chromatographic method with UV detection. RESULTS: Co-administration with ketoconazole markedly increased the mean values of mefloquine AUC0-t, t(1/2), and Cmax when compared with mefloquine alone by 79% (P < 0.001), 39% (P < 0.05) and 64% (P < 0.001) respectively. The AUC0-t , and Cmax of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0.05) and 31% (P < 0.05), respectively when compared with mefloquine alone. CONCLUSIONS: Co-administration with ketoconazole increased plasma mefloquine concentrations in healthy human volunteers. One of possible mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloquine is co-administered with ketoconazole, drug-drug interactions should be recognized and the dose of mefloquine should be adjusted to maximize the therapeutic efficacy and to reduce the cost of therapy.     

Effect of CYP3A5*3 genotype on serum carbamazepine concentrations at steady-state in Korean epileptic patients

Background and Objective:  Carbamazepine (CBZ) is metabolized mainly by the CYP3A family of enzymes, which includes CYP3A4 and CYP3A5. Several studies have suggested that the CYP3A5*3 genotype influences the pharmacokinetics of CYP3A substrates. The present study aimed to assess the effect of the CYP3A5*3 genotype on serum concentration of CBZ at the steady-state in Korean epileptic patients.
Method:  The serum concentrations of CBZ in 35 Korean epileptic patients were measured and their CYP3A5 genotype was determined. Fourteen patients were CYP3A5 expressors (two for CYP3A5*1/*1 and 12 for CYP3A5*1/*3 ) and 21 patients were CYP3A5 non-expressors ( CYP3A5*3/*3 ). Dose-normalized concentrations (mean ± SD) of CBZ were 9·9 ± 3·4 ng/mL/mg for CYP3A5 expressors and 13·1 ± 4·5 ng/mL/mg for CYP3A5 non-expressors ( P  = 0·032). The oral clearance of CBZ was significantly higher in CYP3A5 non-expressors than that of CYP3A5 expressors (0·056 ±0·017 L/h/kg vs. 0·040 ± 0·014 L/h/kg, P  = 0·004). The CYP3A5 genotype affected the CBZ concentrations in Korean epileptic patients and is a factor that may contribute to inter-individual variability in CBZ disposition in epileptic patients.     

CYP2D6 Phenotype-Specific Codeine Population Pharmacokinetics

Codeine's metabolic fate in the body is complex, and detailed quantitative knowledge of it, and that of its metabolites is lacking among prescribers. We aimed to develop a codeine pharmacokinetic pathway model for codeine and its metabolites that incorporates the effects of genetic polymorphisms. We studied the phenotype-specific time courses of plasma codeine, codeine-6-glucoronide, morphine, morphine-3-glucoronide, and morphine-6-glucoronide. A codeine pharmacokinetic pathway model accurately fit the time courses of plasma codeine and its metabolites. We used this model to build a population pharmacokinetic codeine pathway model. The population model indicated that about 10% of a codeine dose was converted to morphine in poor-metabolizer phenotype subjects. The model also showed that about 40% of a codeine dose was converted to morphine in EM subjects, and about 51% was converted to morphine in ultrarapid-metabolizers. The population model further indicated that only about 4% of MO formed from codeine was converted to morphine-6-glucoronide in poor-metabolizer phenotype subjects. The model also showed that about 39% of the MO formed from codeine was converted to morphine-6-glucoronide in extensive-metabolizer phenotypes, and about 58% was converted in ultrarapid-metabolizers. We conclude, a population pharmacokinetic codeine pathway model can be useful because beyond helping to achieve a quantitative understanding the codeine and MO pathways, the model can be used for simulation to answer questions about codeine's pharmacogenetic-based disposition in the body. Our study suggests that pharmacogenetics for personalized dosing might be most effectively advanced by studying the interplay between pharmacogenetics, population pharmacokinetics, and clinical pharmacokinetics.     

Population Pharmacokinetics of Transdermal Fentanyl in Patients With Cancer-Related Pain

ABSTRACT

Determining the appropriate dose of transdermal fentanyl (TDF) for the alleviation of cancer pain requires determining the factors causing variations in serum fentanyl concentration after TDF treatment. The objective of this study was to identify these factors and incorporate them into a formula that can be used to predict serum fentanyl concentration after application of a TDF patch. Blood samples of cancer patients treated with a TDF patch for the alleviation of pain were collected at 24, 48, and 72 hours after application to evaluate population pharmacokinetics using the nonlinear mixed-effect model (NONMEM). Based upon this evaluation, Child-Pugh Score and use of a cytochrome P450 3A4 (CYP3A4) inducer were identified as the most significant factors in variations in serum fentanyl concentration and incorporated into the following Final Model formula: CL_fenta (L/h) = 3.53 × (15 ? Child-Pugh Score) × (1 + 1.38 × use or no use of CYP3A4 inducer). Bootstrap evaluation of the Final Model revealed a high convergence rate, suggesting that the model formula is a reliable and useful tool for determining TDF dose for the alleviation of cancer pain.     

Subcutaneous Sumatriptan Pharmacokinetics: Delimiting the Monoamine Oxidase Inhibitor Effect

(Headache 2010;50:249‐255) Background.— The absolute bioavailability of subcutaneous (s.c.) sumatriptan is 96‐100%. The decay curve for plasma concentration after 6 mg s.c. sumatriptan (ie, after T_max = about 0.2 hours) includes a large distribution component. Metabolism by monoamine oxidase‐A (MAO‐A) leads to about 40% of the s.c. dose appearing in the urine as the inactive indole acetic acid. Product labeling states that co‐administration of an inhibitor of MAO‐A (a MAOI‐A) causes a 2‐fold increase in sumatriptan plasma concentrations, and a 40% increase in elimination half‐life. Objective.— The objective of this study is to determine whether MAOI‐A therapy should deter the use of 6 mg s.c. sumatriptan on pharmacokinetic grounds. Methods.— Summary pharmacokinetic data were taken from the literature and from GlaxoSmithKline (GSK) study C92‐050. Half‐times were converted into rate constants, which were then used in a parsimonious compartmental model (needing only 3 simultaneous differential equations). Acceptance criteria for the model included observed plasma sumatriptan concentrations at T_max, 1, 2, and 10 hours post‐dose. A set of 1000 concentration measurements at a resolution of 36 seconds was generated. The model was then perturbed with elimination constants observed during concomitant moclobemide administration, creating a second set of concentration measurements. The 2 sets were then plotted, examined for their differences, and integrated for a second time to obtain and compare areas under the curve (AUCs). Results.— The greatest absolute difference between the 2 sets of measurements was 2.85 ng/mL at t = 2.95 hours. A 2‐fold difference between the 2 sets occurred only after t = 5.96 hours, when the concentration in the presence of the MAOI‐A was 3.72 ng/mL (or <4% of C_max). At t = 10 hours, the concentrations in both sets were <1 ng/mL (ie, below the lower limit of assay quantitation), and AUC_0‐10h was 97.4 and 117 ng.hour/mL in the absence and presence of the MAOI‐A. Conclusions.— There are no pharmacokinetic grounds to deter co‐administration of an MAOI‐A and subcutaneous sumatriptan. The dominance of the distribution phase and completeness of absorption of a 6 mg dose of s.c. sumatriptan explains the trivial effect size of the MAOI‐A on plasma sumatriptan concentrations. Importantly, these findings should not be extrapolated to other routes of administration for sumatriptan.     

Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers

What is known and objective: Risperidone is an atypical antipsychotic agent used for the treatment of schizophrenia. It is mainly metabolized by human cytochrome P450 CYP2D6 and partly by CYP3A4 to 9‐hydroxyrisperidone. Ketoconazole is used as a CYP3A4 inhibitor probe for studying drug–drug interactions. We aim to investigate the effect of ketoconazole on the pharmacokinetics of risperidone in healthy male volunteers. Methods: An open‐label, randomized, two‐phase crossover design with a 2‐week washout period was performed in 10 healthy male volunteers. The volunteers received a single oral dose of 2 mg of risperidone alone or in combination with 200 mg of ketoconazole, once daily for 3 days. Serial blood samples were collected at specific periods after ingestion of risperidone for a period of 96 h. Plasma concentrations of risperidone and 9‐hydroxyrisperidone were determined using a validated HPLC–tandem mass spectrometry method. Results and discussion: After pretreatment with ketoconazole, the clearance of risperidone decreased significantly by 34·81 ± 15·10% and the T_1/2 of risperidone increased significantly by 28·03 ± 40·60%. The AUC_0–96 and AUC_0–∞ of risperidone increased significantly by 66·61 ± 43·03% and 66·54 ± 39·76%, respectively. The Vd/f of risperidone increased significantly by 39·79 ± 53·59%. However, the C_max and T_max of risperidone were not significantly changed, indicating that ketoconazole had minimal effect on the absorption of risperidone. The C_max, T_max and T_1/2 of 9‐hydroxyrisperidone did not decrease significantly. However, the Cl/f of 9‐hydroxyrisperidone increased significantly by 135·07 ± 124·68%, and the Vd/f of 9‐hydroxyrisperidone decreased significantly by 29·47 ± 54·64%. These changes led to a corresponding significant decrease in the AUC_0–96 and AUC_0–∞ of 9‐hydroxyrisperidone by 47·76 ± 22·39% and 48·49 ± 20·03%, respectively. Ketoconazole significantly inhibited the metabolism of risperidone through the inhibition of hepatic CYP3A4. Our results suggest that besides CYP2D6, CYP3A4 contributes significantly to the metabolism of risperidone. What is new and Conclusion: The pharmacokinetics of risperidone was affected by the concomitant administration of ketoconazole. If a CYP3A4 inhibitor is used concomitantly with risperidone, it is necessary for the clinicians to monitor their patients for signs of adverse drug reactions.     

Pharmacokinetic Interaction Between Rosuvastatin and Telmisartan in Healthy Korean Male Volunteers: A Randomized,Open-label,Two-period,Crossover, Multiple-dose Study

Purpose

Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and telmisartan, an angiotensin receptor blocker, are commonly prescribed in combination for the treatment of dyslipidemia accompanied by hypertension. However, the nature of the pharmacokinetic interaction between the 2 drugs is not clearly understood. The goal of the present study was to investigate the pharmacokinetic drug–drug interaction between rosuvastatin and telmisartan in a healthy Korean population.

Methods

This was a randomized, 2-part, open-label, 2-period, crossover, multiple-dose study, with each part composed of different subjects between the ages of 20 and 55 years. In part 1, each subject received rosuvastatin 20 mg with and without telmisartan 80 mg once daily for 6 consecutive days. In part 2, each subject received telmisartan 80 mg with and without rosuvastatin 20 mg once daily for 6 consecutive days. In both parts, there was a 16-day washout period between mono- and coadministration. Blood samples were collected up to 72 hours after the last dose. Adverse events (AEs) were evaluated through interviews and physical examinations.

Findings

In part 1, the 90% CIs of the geometric mean ratios for the primary pharmacokinetic parameters for coadministration of the 2 drugs to monoadministration of each drug were 1.0736–1.2932 for AUC_τ and 1.7442–2.3229 for C_max,ss for rosuvastatin and 0.9942–1.1594 for AUC_τ and 1.3593–1.7169 for C_max,ss for N-desmethyl rosuvastatin, whereas in part 2, the CIs were 1.0834–1.2672 for AUC_τ and 1.1534–1.5803 for C_max,ss for telmisartan. The most frequently noted AE was cough in part 1, which occurred in 2 subjects receiving the combination therapy, and oropharyngeal pain in part 2, which occurred in 3 subjects receiving the combination therapy. All reported AEs were mild or moderate, and there was no significant difference in incidence between the treatments.

Implications

These findings demonstrated that rosuvastatin and telmisartan mutually affected each other’s pharmacokinetics, suggesting a possibility of drug–drug interaction. However, based on dose–response characteristics of the 2 drugs and previous results from other interaction studies, the degree of drug interaction observed in this study was not regarded as clinically significant. All treatments were well tolerated, with no serious AEs observed. ClinicalTrials.gov identifier: NCT01992601.     

Effects of clarithromycin on the pharmacokinetics of tacrolimus and expression of CYP3A4 and P-glycoprotein in rats

The objective of this study was to investigate the effect of clarithromycin on the pharmacokinetics of tacrolimus in rats and better understand its mechanism. In the control group (n = 6), rats received a single oral dose of 1 mg tacrolimus on day 6. In the experimental group (n = 6), rats received 0.25 g of clarithromycin daily for five consecutive days and then a single oral dose of 1 mg tacrolimus on day 6. Orbital venous blood (250 μL) was collected at 0, 0.25, 0.50, 0.75, 1, 2, 4, 8, 12, and 24 h before and after tacrolimus administration. Blood drug concentrations were detected via mass spectrometry. Small intestine and liver tissue samples were collected after rats were euthanized via dislocation, and CYP3A4 and P-glycoprotein (P-gp) protein expression was determined using western blotting. Clarithromycin increased the blood tacrolimus concentration and affected its pharmacokinetic properties in rats. Compared with those in the control group, the AUC_0–24, AUC_0–∞, AUMC_(0–t), and AUMC_(0–∞) of tacrolimus in the experimental group were significantly increased, whereas the CLz/F was significantly lower (P < 0.01). Simultaneously, clarithromycin significantly inhibited CYP3A4 and P-gp expression in the liver and intestine. Protein expression of CYP3A4 and P-gp in the liver and the intestinal tract was significantly downregulated in the intervention group compared with that in the control group. Clarithromycin significantly inhibited the protein expression of CYP3A4 and P-gp in the liver and intestine, thereby increasing the mean blood concentration and significantly increasing the AUC of tacrolimus.     

Pharmacokinetic Interaction Between Rosuvastatin and Metformin in Healthy Korean Male Volunteers: A Randomized,Open-label, 3-period,Crossover, Multiple-dose Study

Purpose

Rosuvastatin is indicated for hypercholesterolemia or dyslipidemia and metformin mainly for type 2 diabetes. These 2 drugs are frequently prescribed in combination due to the high comorbidity of the 2 diseases. However the nature of pharmacokinetic interaction between the 2 drugs has not been previously investigated. The purpose of our study was to investigate the pharmacokinetic interaction between rosuvastatin and metformin in healthy Korean male volunteers.

Methods

This was a randomized, open-label, 6-sequence, 3-period, crossover, multiple-dose study. Eligible subjects, aged 20 to 50 years and within 20% of the ideal body weight, received 1 of the following 3 treatments for each period once daily for 5 consecutive days with a 10-day washout period between the treatments: monoadministration of rosuvastatin 10 mg tablet, monoadministration of metformin 750 mg tablet, and coadministration of rosuvastatin 10 mg tablet with metformin 750 mg tablet. Blood samples were collected up to 72 hours after the last dose and pharmacokinetic parameters for rosuvastatin and metformin were compared between combination and monotherapy. Adverse events were investigated and evaluated based on subject interviews and physical examinations.

Findings

Among the 36 enrolled subjects, 31 completed the study. The coadministration of rosuvastatin with metformin produced a significant pharmacokinetic interaction in rosuvastatin C_ss,max, with the 90% CI for the geometric mean ratio (coadministration:monoadministration) being 110.27% to 136.39% (P = 0.0029), whereas no significant interaction was observed in rosuvastatin AUC_tau, yielding the 90% CI of 104.41% to 118.95%. When metformin was coadministered with rosuvastatin, no significant pharmacokinetic interaction was observed for C_ss,max and AUC_tau of metformin, yielding the 90% CIs of the geometric mean ratio for coadministration to monoadministration as 87.38% to 102.54% and 86.70% to 99.08%, respectively. Overall, 19 mild and 1 moderate adverse events occurred in 12 subjects, with no significant differences in the incidence among the 3 treatments.

Implications

Although the C_ss,max of rosuvastatin was significantly influenced by coadministration with metformin, the degree of interaction seen was considered clinically insignificant, with no significant interaction observed in the other pharmacokinetic measures between the 2 drugs. These results imply that drug effects of rosuvastatin and metformin will also not be significantly influenced by coadministration of the 2 drugs. All treatments were well tolerated and no serious adverse events occurred. ClinicalTrials.gov identifier: NCT01526317.     

细胞色素P450 3A4在乳腺癌组织中的表达及其临床意义

目的研究细胞色素P450 3A4(CYP3A4)在乳腺癌组织中的表达及其与化疗反应间的关系,并对其表达差异的遗传基础进行初步探讨。方法乳腺癌病例组包括40例单纯手术患者3、6例新辅助化疗后手术患者和200例辅助性化疗患者;其中新辅助化疗患者接受以紫杉醇为基础的化疗。利用实时荧光RT-PCR检测手术患者癌组织及其癌旁组织中CYP3A4 mRNA的表达,连接依赖性SNP技术检测CYP3A4*18基因分型。结果 CYP3A4在大多数乳腺癌组织及其癌旁组织中均有表达;在40例单纯手术患者中,其表达水平(ΔCt)分别为21.8(18.7-24.2)和21.3(18.0-23.1);36例新辅助化疗患者中,其表达水平分别为20.7(16.2-24.7)和21.1(17.0-23.8);癌与癌旁组织间的比较无统计学差异(P0.05)。新辅助化疗有反应者(22例)CYP3A4表达水平为22.0(19.3-25.0)明显低于无反应者(14例为19.1(14.8-22.0);Z=-2.08,P=0.038]。本组乳腺癌手术患者CYP3A4*18变异频率过低[1/(76×2),0.66%],未能与CYP3A4表达水平和化疗反应进行关联分析。结论乳腺癌组织可表达CYP3A4,其表达水平的高低可能与基于紫杉类药物的化疗反应相关。     

Lack of a Clinically Significant Pharmacokinetic Interaction Between Pregabalin and Thioctic Acid in Healthy Volunteers

Purpose

Pregabalin and thioctic acid are likely to be used concomitantly for the treatment of painful diabetic neuropathy. In this study, the pharmacokinetic interaction between pregabalin and thioctic acid was investigated at steady state.