Pharmacokinetic Drug Interaction Study Research Articles

A rapid and sensitive LC-MS/MS method for quantifying oxycodone, noroxycodone, oxymorphone and noroxymorphone in human plasma to support pharmacokinetic drug interaction studies of oxycodone.

A sensitive and reliable LC-MS/MS method was developed and validated for the quantification of oxycodone and metabolites in human plasma. The method has a runtime of 6min and a sensitivity of 0.1μg/L for all analytes. Sample preparation consisted of protein precipitation. Separation was performed on a Kinetix biphenyl column (2.1 × 100 mm, 1.7μm), using ammonium formate 5mm in 0.1% aqueous formic acid and methanol LC-MS grade 100% in gradient elution at a flow rate of 0.4ml/min. Detection was performed in multiple reaction monitoring mode using positive electrospray ionization. The method was linear over the calibration range of 0.1-25.0μg/L for oxycodone, noroxycodone and noroxymorphone and 0.1-5.0μg/L for oxymorphone. The method demonstrated good performance in terms of intra- and interday accuracy (86.5-110.3%) and precision (CV 1.7-9.3%). The criteria for the matrix effect were met (CV < 15%) except for noroxymorphone, for which an additional method was applied to compensate for the matrix effect. Whole blood samples were stable for 4h at room temperature. Plasma samples were stable for 24 h at room temperature and 3months at -20°C. Furthermore, the method was successfully applied in a pharmacokinetic drug interaction study of oxycodone and enzalutamide in patients with prostate cancer.

Development and validation of a sensitive LC-MS/MS method for simultaneous analysis of clopidogrel and simvastatin and their main metabolites in beagles: Application to pharmacokinetic drug interactions.

Clopidogrel (CLP) and simvastatin (SV) are commonly used in combination therapies as anti-cardiovascular drugs. However, the effect of coadministration on the absorption and metabolism of the two drugs in vivo is not clear. This study developed and validated an LC-MS/MS method for the simultaneous determination of CLP, clopidogrel carboxylic acid (CLPCA), 2-oxo-clopidogrel (2-O-CLP), SV, and simvastatin hydroxy acid (SVA) in beagle plasma. Chromatographic separation was achieved on an InfinityLab Poroshell 120 SB-C8 column (2.1 × 100 mm, 2.7μm) using methanol and 0.1% formic acid in water as the mobile phase at a flow rate of 0.3mL/min in gradient mode. The lower limits of quantification are 0.1, 0.8, 0.05, 0.05, and 0.05 ng/mL for CLP, CLPCA, 2-O-CLP, SV, and SVA, respectively. The selectivity, linearity, accuracy, precision, extraction recovery, matrix effect, and stability were validated within acceptable criteria. This method was successfully applied to the pharmacokinetic drug interaction study between CLP and SV, and the results revealed that combined administration affected the metabolic rate of CLP, SV, and their metabolites. This study is the first to detect CLP, CLPCA, 2-O-CLP, SV, and SVA simultaneously.

Cytochrome P450 3A4-mediated pharmacokinetic interaction study between tadalafil and canagliflozin using high-performance thin-layer chromatography.

Diabetes is a known risk factor for sexual dysfunction in men; diabetic men have an increased risk of erectile dysfunction compared to non-diabetic men. Canagliflozin is one of the common antidiabetic drugs that is readily used in the treatment of type-2 diabetes. Concomitantly phosphodiesterase 5 inhibitors, such as tadalafil, can be given to the patient to alleviate erectile dysfunction. Canagliflozin is reported to be one of the cytochrome P450 3A4 enzyme inhibitors, that might seriously influence blood concentration levels of tadalafil but there is no study till now, discussing this interaction. Therefore, a fast, simple, and sensitive high-performance thin-layer chromatographic method was developed, validated, and applied for the simultaneous determination of tadalafil and canagliflozin in spiked and real human plasma. The limit of detection for tadalafil was 0.14ng/band and for canagliflozin was 0.16ng/band. The limit of quantitation value for tadalafil was 0.43ng/band and for canagliflozin was 0.47ng/band. Tadalafil and canagliflozin were determined simultaneously in real human plasma using the described procedure and the method was applied for in vivo pharmacokinetic drug interaction study between the studied drugs, which proved significant interaction between them when administered simultaneously.

A Simple UPLC/MS-MS Method for Simultaneous Determination of Lenvatinib and Telmisartan in Rat Plasma, and Its Application to Pharmacokinetic Drug-Drug Interaction Study.

Lenvatinib is a multi-targeted tyrosine kinase inhibitor that inhibits tumor angiogenesis, but hypertension is the most common adverse reaction. Telmisartan is an angiotensin receptor blocker used to treat hypertension. In this study, a simple ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of lenvatinib and telmisartan, and it was applied to the pharmacokinetic drug interaction study. Plasma samples were treated with acetonitrile to precipitate protein. Water (containing 5 mM of ammonium acetate and 0.1% formic acid) and acetonitrile (0.1% formic acid) were used as the mobile phases to separate the analytes with gradient elution using a column XSelect HSS T3 (2.1 mm × 100 mm, 2.5 μm). Multiple reaction monitoring in the positive ion mode was used for quantification. The method was validated and the precision, accuracy, matrix effect, recovery, and stability of this method were reasonable. The determination of analytes was not interfered with by other substances in the blank plasma, and the calibration curves of lenvatinib and telmisartan were linear within the range of 0.2–1000 ng/mL and 0.1–500 ng/mL, respectively. The results indicate that lenvatinib decreased the systemic exposure of telmisartan. Potential drug interactions were observed between lenvatinib and telmisartan.

LIQUID CHROMATOGRAPHY TANDEM MASS SPECTROMETRY DETERMINATION METHOD OF BENCYCLOQUIDIUM BROMIDE: APPLICATION TO DRUG INTERACTION STUDY IN HUMAN

Objective: This study was conducted to develop a sensitive and effective LC-MS/MS method for the determination of bencycloquidium bromide (BCQB) and its application in pharmacokinetic drug interaction study between BCQB and paroxetine.&#x0D; Methods: The chromatographic separation was performed on Hedera ODS-2 C18 column with a mobile phase consisted of acetonitrile-10 mmol/l ammonium acetate containing 0.2% acetic acid (33:67, v/v) at 550 μl/min, and the plasma samples were processed using solid-phase extraction. The MS/MS transitions were m/z 330.2 → 142.0 for BCQB and m/z 344.2 → 156.1 for the I. S in positive ESI mode.&#x0D; Results: The validated method was linear over the concentration range of 2-1200 pg/ml with the correlation coefficient r2&gt;0.998. The intra-and inter-batch precisions of the assay were lower than 8.2% and 9.1%, respectively. The lower limit of quantification (LLOQ) was 2 pg/ml. The stability data at different storage conditions of BCQB were within±5% RE. The mean AUC0-36 of BCQB was increased by approximately 33%, after the administration of BCQB alone and upon co-administration with paroxetine during the drug interaction study.&#x0D; Conclusion: The LC-MS/MS method validated in this study was robust, reproducible, accurate, precise and reliable and was successfully applied in the pharmacokinetic drug interaction studies.

CYP3A4 mediated pharmacokinetics drug interaction potential of Maha-Yogaraj Gugglu and E, Z guggulsterone

Maha yogaraja guggulu (MYG) is a classical herbomineral polyherbal formulation being widely used since centuries. The aim of this study was to investigate the effect of MYG formulation and its major constituents E & Z guggulsterone on CYP3A4 mediated metabolism. In vitro inhibition of MYG and Guggulsterone isomers on CYP3A4 was evaluated by high throughput fluorometric assay. Eighteen Adult male Sprague–Dawley rats (200 ± 25 g body weight) were randomly divided into three groups. Group A, Group B and Group C were treated with placebo, MYG and Standard E & Z guggulsterone for 14 days respectively by oral route. On 15th day, midazolam (5 mg/kg) was administered orally to all rats in each group. Blood samples (0.3 mL) were collected from the retro orbital vein at 0.25, 0.5, 0.75, 1, 2, 4, 6, 12 and 24 h of each rat were collected. The findings from the in vitro & in vivo study proposed that the MYG tablets and its guggulsterone isomers have drug interaction potential when consumed along with conventional drugs which are CYP3A4 substrates. In vivo pharmacokinetic drug interaction study of midazolam pointed out that the MYG tablets and guggulsterone isomers showed an inhibitory activity towards CYP3A4 which may have leads to clinically significant interactions.

Development and validation of a high performance liquid chromatography method to determine nevirapine in plasma in a resource-limited setting.

BackgroundThere are several instances where nevirapine pharmacokinetic monitoring may be useful, such as in special populations or pharmacokinetic drug interaction studies that require the ascertainment of nevirapine pharmacokinetics in the sub-Saharan region.ObjectivesThe main aim of this study was to produce a validated, sustainable and relevant nevirapine assay method that meets bio-analytical regulatory requirements.MethodsThe developed method utilised a Waters 2795 Alliance high performance liquid chromatography system with a 2996 photo diode array detector, an Atlantis dC18 5 micron, 3.9 mm × 150 mm analytical column and a gradient flow rate of 1 mL/min. Ultraviolet detection data were collected from 210 nm to 400 nm, extracted at 260 nm, and processed for nevirapine and internal standard peak height responses.ResultsThe method proved to be linear (R2 0.995), precise (+1.92% – +9.69%) and accurate (-9.70% – 12.0%). Recovery for the analyte and internal standard was between 98.8% and 114%. The method showed good specificity as no interferences were caused by common African traditional medicines, anti-tuberculosis medications or other concomitant antiretrovirals nor endogenous components.ConclusionThe method is reproducible, relevant to our setting and uses considerably low plasma volumes with preservation of some consumables, a desirable key factor in a resource-limited setting.

In vitro pharmacokinetic drug interaction study Of combination of antiretroviral and Antimalarial drugs

In vitro pharmacokinetic drug interaction study Of combination of antiretroviral and Antimalarial drugs

Simultaneous determination of rosuvastatin, naringin and naringenin in rat plasma by RRLC-MS/MS and its application to a pharmacokinetic drug interaction study.

A rapid resolution liquid chromatography tandem mass spectrometry method was developed and validated for simultaneous determination of rosuvastatin, naringin and naringenin in rat plasma. Chromatographic separation of analytes and internal standard (fluvastatin for rosuvastatin, while isoquercitrin for naringin and naringenin) was performed on Agilent Poroshell 120 EC-C18 column (3.0 × 50 mm, 2.7 μm) using gradient elution with a mobile phase of methanol and water, both with 0.1% formic acid (v/v). The detection was operated in multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 579.1→270.8 for naringin, m/z 270.9→150.7 for naringenin, m/z 463.1→299.8 for isoquercitrin in negative ionization mode, and m/z 482.2→258.1 for rosuvastatin, m/z 412.1→224.1 for fluvastatin in positive ionization mode. Polarity switch (negative-positive-negative ionization mode) was performed in a total runtime of 5.0 min. The method was validated over a concentration range of 10-2,000 ng/mL for the above three analytes. The intra-day and inter-day precisions and accuracies of the quality control samples at low, medium and high concentration levels exhibited relative standard deviations <10% and the accuracy values ranged from -7.2% to 8.4%. The proposed method was successfully applied to the pharmacokinetic drug interaction study of rosuvastatin combined with naringin in rats.

Effects of Danshen capsules on the pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers

Nowadays, the Herb-drug combination is becoming increasingly popular in China. However, the possible interaction induced by their combination was examined rarely. The aim of this study was to investigate the effect of multi-dose administration of Danshen capsules on clopidogrel pharmacokinetics and pharmacodynamics in healthy volunteers. A sequential, open-label, and two-period pharmacokinetic drug interaction study was designed to compare clopidogrel pharmacokinetic parameters before and after 7 days of administration of Danshen capsules in twenty healthy male volunteers. Co-administration of multiple doses of Danshen capsules caused increases in apparent oral clearance of clopidogrel and its metabolite by 96.5% and 73.7% and apparent volume of distribution by 94.2% and 75.1%, corresponding declines in Cmax by 41.7% and 32.9%, AUC0-t by 50.3% and 41.8%, and AUC0-∞ by 49.3% and 41.5% in human volunteers, respectively. Corresponding pharmacokinetic findings, co-administration of Danshen capsules with clopidogrel decreased the antiplatelet activity compared with individual agents. The results suggested that multiple dose administration of Danshen capsules could induce cytochrome P450 (CYP) isoenzymes, thereby increasing the clearance of clopidogrel. Therefore, caution should be taken when Danshen products containing lipophilic components are used in combination with therapeutic drugs metabolized by CYP3A4.

Mechanism of in-vitro inhibition of UGT1A1 by paritaprevir

The direct-acting protease inhibitor paritaprevir is a new pharmaco-logic option available for treatment of chronic hepatitis C (HCV). Paritaprevir is reported to inhibit human UGT 1A1, but the mechanism of inhibition and its possible clinical consequences are not established. Our objective was to evaluate the in-vitro metabolic interaction between paritaprevir and the oral contraceptive steroid ethinyl estradiol (EE), a UGT 1A1 substrate. Enzyme kinetic parameters were determined using human liver microsomes for the biotransformation of EE to its glucuronide metabolites, and the potency and mechanism of inhibition by paritaprevir. Probenecid was used as a reference inhibitor for purposes of assay validation. The underlying pattern of EE kinetics was complex, with evidence of substrate inhibition. The in-vitro inhibition constant (Ki ) value for paritaprevir vs EE on average was 20μm and was consistent with a competitive inhibition mechanism. The ratio of in-vivo maximum plasma concentration of paritaprevir to in-vitro Ki was <0.1. Paritaprevir is an in-vitro inhibitor of UGT 1A1. However, the in-vitro Ki value relative to maximum clinical plasma concentrations is below the threshold to trigger a recommendation for pharmacokinetic drug interaction studies.

Pharmacokinetic drug interaction study between overactive bladder drugs mirabegron and tolterodine in Japanese healthy postmenopausal females

Mirabegron, the first selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), inhibits cytochrome P450 isozyme CYP2D6. This study was performed in Japanese healthy postmenopausal female volunteers to assess any pharmacokinetic drug interaction between mirabegron and tolterodine, another OAB drug and a sensitive substrate of CYP2D6. Tolterodine 4 mg was orally administered from Days 1–7 and co-administered with mirabegron 50 mg from Days 8–14. Mirabegron 50 mg increased maximum concentration (Cmax) and area under the concentration-time curve from zero to 24 h after dosing (AUC24h) of tolterodine by 2.06-fold (90% confidence interval [CI] 1.81, 2.34) and 1.86-fold (90% CI 1.60, 2.16), respectively, and increased Cmax and AUC24h of the metabolite 5-hydroxymethyl tolterodine by 1.36-fold (90% CI 1.26, 1.47) and 1.25-fold (90% CI 1.15, 1.37), respectively. This suggested a weak pharmacokinetic drug interaction between mirabegron and tolterodine. Mean change from baseline of Fridericia's QT correction formula (ΔQTcF) was slightly higher on Day 14 than on Day 7. No subject had QTcF >480 msec or ΔQTcF >60 msec. All the treatment-emergent adverse events were mild. Mirabegron 50 mg was considered to be safe and well tolerated when coadministered with tolterodine 4 mg in healthy postmenopausal female volunteers.

Pharmacokinetic and Pharmacodynamic Drug Interaction Study of Piragliatin, a Glucokinase Activator, and Glyburide, a Sulfonylurea, in Type 2 Diabetic Patients.

A glucokinase activator and a sulfonylurea might be coprescribed to synergize treatment success for type 2 diabetes (T2D). This clinical pharmacology study was designed to investigate the potential glucose-lowering effect or pharmacodynamic (PD), pharmacokinetic (PK), and safety/tolerability interactions between piragliatin and glyburide in T2D patients already taking glyburide but not adequately controlled. This was an open-label, multiple-dose, 3-period, single-sequence crossover design: on days -1, 6, and 12, PD and PK samples were drawn with glyburide alone (period 0), piragliatin + glyburide (period 1), and piragliatin alone (period 2) treatments. The glucose-lowering effect, including fasting plasma glucose (FPG), of piragliatin was more pronounced when it was administered concomitantly with glyburide as compared to piragliatin or glyburide administered alone. However, this enhancement cannot be explained by a potential PK interaction between piragliatin and glyburide. Other than hypoglycemia, there were no clinically relevant safety findings. Thus, the enhanced PD effect warrants further investigation to define the optimal dose combination between glucokinase activators and sulfonylureas with regard to efficacy, safety, and tolerability.

Studies on Pharmacokinetic Drug Interaction Potential of Vinpocetine.

BackgroundVinpocetine, a semi-synthetic derivative of vincamine, is a popular dietary supplement used for the treatment of several central nervous system related disorders. Despite its wide use, no pharmacokinetic drug interaction studies are reported in the literature. Due to increasing use of dietary supplements in combination with conventional drugs, the risk of adverse effects is on the rise. As a preliminary step to predict a possibility of drug interaction during concomitant use of vinpocetine and conventional drugs, this study was carried out to evaluate the effects of vinpocetine on three main regulators of pharmacokinetic drug interactions namely, cytochromes P450 (CYPs), P-glycoprotein (P-gp), and Pregnane X receptor (PXR).MethodsInhibition of CYPs was evaluated by employing recombinant enzymes. The inhibition of P-gp was determined by calcein-AM uptake method in transfected and wild type MDCKII cells. Modulation of PXR activity was monitored through a reporter gene assay in HepG2 cells.ResultsVinpocetine showed a strong inhibition of P-gp (EC50 8 μM) and a moderate inhibition of recombinant CYP3A4 and CYP2D6 (IC50 2.8 and 6.5 μM) with no activity towards CYP2C9, CYP2C19 and CYP1A2 enzymes. In HLM, competitive inhibition of CYP3A4 (IC50 54 and Ki 19 μM) and non-competitive inhibition of CYP2D6 (IC50 19 and Ki 26 μM) was observed. Activation of PXR was observed only at the highest tested concentration of vinpocetine (30 μM) while lower doses were ineffective.ConclusionStrong inhibition of P-gp by vinpocetine is indicative of a possibility of drug interactions by altering the pharmacokinetics of drugs, which are the substrates of P-gp. However, the effects on CYPs and PXR indicate that vinpocetine may not affect CYP-mediated metabolism of drugs, as the inhibitory concentrations are much greater than the expected plasma concentrations in humans.

Investigation on modulation of human P-gp by multiple doses of Radix Astragali extract granules using fexofenadine as a phenotyping probe

EthnopharmacologyHerb–drug interactions may potentially affect drug efficacy and/or the likelihood of adverse drug reactions. Radix Astragali (RA) extract formulation is usually prescribed for long-term use for patients with immunodeficiency, diabetes, nephropathy or cardiovascular diseases. Its use in combination with P-glycoprotein (P-gp) substrates is possible in clinical practice. Currently there is little knowledge about whether concomitant use of RA extract has an influence on disposition of P-gp substrate. Aim of the studyThis study was to investigate whether continuous and multiple doses of RA extract granules had modulatory effects on human P-gp. Material and methodsA randomised, placebo-controlled, two-period crossover pharmacokinetic drug interaction study was conducted in healthy Chinese volunteers. Fexofenadine was used as a P-gp phenotyping probe. Fourteen volunteers received RA extract granules or placebo (4g bid) for 7 days and then received a single oral dose of 120mg fexofenadine. Fexofenadine plasma concentrations were determined by HPLC. Pharmacokinetic parameters were calculated by non-compartmental method and bioequivalence evaluation was performed. ResultsPharamcokinetic parameters in the placebo phase were as follows: T1/2 (3.75±1.47h), Cmax (745.11±137.41μg/L), Tmax (2.25±0.47h), AUC(0−t) (3894.27±923.45μgh/L), AUC(0−∞) (3993.84±912.97μgh/L). Pharamcokinetic parameters in the RA extract phase were as follows: T1/2 (4.00±1.24h), Cmax (709.44±170.03μg/L), Tmax (2.21±0.51h), AUC(0−t) (3832.72±1077.60μgh/L), AUC(0−∞) (3983.53±1019.83μgh/L). The influence of RA extract on fexofenadine Cmax and AUC lacks statistical significance. Fexofenadine in the two phases were bioequivalent. In the placebo phase, T1/2 of fexofenadine in ABCB1 3435T mutation allele carriers was longer compared to ABCB1 3435CC carriers (4.43±1.44h vs. 2.54±0.21h, p<0.05). However, RA extract pretreatment abolished such genotype-related difference due to the lengthened T1/2 in ABCB1 3435CC carriers. There was no association of the C3435T polymorphism with Cmax and AUC(0−t) in subjects with two pretreatments. ConclusionOne-week administration of RA extract granules did not have a statistically significant impact on systematic exposure to fexofenadine, suggesting that RA extract is not a potent modulator of P-gp in vivo. RA extract appears to have ABCB1 C3435T genotype-dependent inhibitory effect on elimination rather than absorption of a P-gp substrate. Further investigations are necessary in patients who receive long-term use of RA extract formulation and combined P-gp substrates, especially in those ABCB1 3435CC carriers.

Heterologous expression of human cytochrome P450 (CYP) 2C19 in Escherichia coli and establishment of RP‐HPLC method to serve as activity marker

In this study, a simple and reliable reverse-phase high-performance liquid chromatography (RP-HPLC) method was established and validated to analyze S-mephenytoin 4-hydroxylase activity of a recombinant CYP2C19 system. This system was obtained by co-expressing CYP2C19 and NADPH-CYP oxidoreductase (OxR) proteins in Escherichia coli (E. coli) cells. In addition to RP-HPLC, the expressed proteins were evaluated by immunoblotting and reduced CO difference spectral scanning. The RP-HPLC assay showed good linearity (r(2) = 1.00) with 4-hydroxymephenytoin concentration from 0.100 to 50.0 μm and the limit of detection was 5.00 × 10(-2) μm. Intraday and interday precisions determined were from 1.90 to 8.19% and from 2.20 to 14.9%, respectively. Recovery and accuracy of the assay were from 83.5 to 85.8% and from 95.0 to 105%. Enzyme kinetic parameters (Km , Vmax and Ki ) were comparable to reported values. The presence of CYP2C19 in bacterial membranes was confirmed by immunoblotting and the characteristic absorbance peak at 450 nm was determined in the reduced CO difference spectral assay. Moreover, the activity level of co-expressed OxR was found to be comparable to that of the literature. As a conclusion, the procedures described here have generated catalytically active CYP2C19 and the RP-HPLC assay developed is able to serve as CYP2C19 activity marker for pharmacokinetic drug interaction study in vitro.

Safety, Tolerability, and Pharmacokinetics of the HIV Integrase Inhibitor Dolutegravir Given Twice Daily With Rifampin or Once Daily With Rifabutin

Cotreatment of tuberculosis (TB) and HIV among coinfected patients is now the standard of care. Rifampin (RIF) is a standard part of TB treatment but is a potent inducer of drug metabolizing enzymes. This study evaluated the effect of RIF or rifabutin (RBT) on the pharmacokinetics of the investigational HIV integrase inhibitor, dolutegravir (DTG). Phase I pharmacokinetic drug interaction study. In arm 1, healthy subjects received 50 mg of DTG once daily for 7 days (period 1), then 50 mg of DTG twice daily for 7 days (period 2), then 50 mg of DTG twice daily together with 600 mg of RIF once daily for 14 days (period 3). In arm 2, subjects received 50 mg of DTG once daily for 7 days (period 1) then 50 mg of DTG once daily together with 300 mg of RBT once daily for 14 days (period 2). PK sampling was performed at the end of each period. In arm 1, comparing period 3 to period 1, the geometric mean ratio (GMR) for the 24-hour area under the time-concentration curve (AUC0-24) was 1.33 [90% confidence interval (CI): 1.14 to 1.53], and the GMR for the trough (Cτ) was 1.22 (90% CI: 1.01 to 1.48). Comparing period 2 to period 1 in arm 2, the GMR for the AUC0-24 was 0.95 (90% CI: 0.82 to 1.10), and the GMR for the Cτ was 0.70 (90% CI: 0.57 to 0.87). Regimens including twice-daily DTG and RIF or once-daily DTG and RBT may represent a new treatment option for patients who require concomitant treatment of HIV and TB.

Effects of Alcohol on the Pharmacokinetics of Morphine Sulfate and Naltrexone Hydrochloride Extended Release Capsules

Although contraindicated, coingestion of alcohol and opioids by patients or drug abusers is a major health concern because of dangerous additive and potentially life-threatening sedative and respiratory effects. In addition, alcohol has been shown to disrupt the extended-release characteristics of certain extended-release opioid formulations, releasing a hazardous amount of opioid over a short time period. Morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT), which contain naltrexone sequestered in each pellet core, are indicated for management of chronic, moderate to severe pain. Sequestered naltrexone is designed for release upon product tampering (crushing) to potentially mitigate morphine-induced subjective effects. This open-label, single-dose, 4-way crossover, pharmacokinetic drug interaction study compared the relative bioavailability of morphine and naltrexone when MS-sNT is administered (under fasting conditions) with increasing doses of alcohol. Thirty-two healthy, opioid-naive adults were randomized to MS-sNT administered with 240 mL of 4%, 20%, or 40% alcohol or water. No drug interaction was found between morphine in MS-sNT and 4% or 20% alcohol. Administration with 40% alcohol did not affect overall morphine exposure but was associated with a 2-fold increase in C(max) and reduction of t(max) from 9 to 4 hours versus MS-sNT taken with water. Naltrexone sequestering was successful in all treatment arms and not affected by coadministration with alcohol over the dose range tested.

Directly acting antivirals for hepatitis C and antiretrovirals

Boceprevir and telaprevir are directly acting antivirals (DAAs) that have recently been licensed for treatment of hepatitis C virus (HCV) infection. Data in both untreated and previously treated patients indicate a significantly increased sustained virological response (SVR) compared with that observed with conventional therapy. However, the advent of DAA therapy poses specific challenges for HCV treatment in terms of managing drug-drug interactions (DDIs). This review aims to provide a comprehensive summary of DDI with the recently licensed DAAs, including pharmacokinetic data and current recommendations made by the manufacturers and with particular reference to antiretrovirals. Potential for DDIs with the DAAs in clinical development and the mechanisms of interaction are also discussed. Targeted pharmacokinetic drug interaction studies have demonstrated that both boceprevir and telaprevir are potent inhibitors of the metabolic enzyme cytochrome P4503A4, making them perpetrators of interactions with co-administered medications which are metabolized by this enzyme. In addition, co-administered medications may affect plasma levels of boceprevir and telaprevir via various mechanisms, some of which remain to be fully elucidated. As a result of DDIs, the concomitant use of some medicines with DAA will be contraindicated, whereas other combinations may require caution, monitoring, or dose modification of the co-administered drug. Management of DDIs with these novel agents will pose a new challenge, and prescriber awareness of the potential for DDIs is fundamental for safe prescribing. Online resources are likely to play a key role in prescriber education and clinical decision-making.

A pharmacokinetic drug interaction study of ceftazidime with clavulanic acid in healthy male Indian subjects

Ceftazidime is a third generation cephalosporin with a broad range of activity. Clavulanic acid is a β-lactamase inhibitor. A fixed dose combination, with the wide spectrum of action of ceftazidime and clavulanic acid’s high stability to β-lactamases has been developed by Ranbaxy Laboratories Limited (India). The present study was planned to predict any interaction between ceftazidime and clavulanic acid which could affect the safety and efficacy of the fixed dose combination. The study was an open label, balanced, randomized two-treatment, two-period, two-sequence, crossover, single-dose comparative pharmacokinetic study under fed conditions. A single intravenous injection of the test product containing a fixed dose combination of ceftazidime 2000 mg and potassium clavulanate 200 mg and the reference product containing ceftazidime 2000 mg only, was administered during each period. Serial blood samples were collected until 12 h post-dose in each period. Ceftazidime and clavulanic acid concentration in pla...