Assessment of drug–drug interaction potential and PBPK modeling of CC-223, a potent inhibitor of the mammalian target of rapamycin kinase

1.?CC-223 was studied in vitro for metabolism and drug–drug interactions (DDI), and in clinic for interaction with ketoconazole.

2.?In vitro, human metabolites of CC-223 included O-desmethyl CC-223 (M1), keto (M2), N-oxide (M3) and imine (M13), with M1 being the most prominent metabolite.

3.?CC-223 was metabolized by CYP2C9 and CYP3A, while metabolism of M1 was mediated by CYP2C8 and CYP3A. Ketoconazole increased CC-223 and M1 exposure by 60–70% in healthy volunteers.

4.?CC-223 (IC₅₀?≥?27?µM) and M1 (IC₅₀?≥?46?µM) were inhibitors of CYP2C9 and CYP2C19 in human liver microsomes. CC-223 and M1 were moderate inducers of CYP3A in human hepatocytes.

5.?CC-223 was a substrate of BCRP, and M1 was a substrate of P-gp and BCRP. CC-223 was an inhibitor of P-gp (IC₅₀?=?3.67?µM) and BCRP (IC₅₀?=?11.7?µM), but at a clinically relevant concentration showed no inhibition of other transporters examined. M1 is a weak inhibitor of P-gp and BCRP.

6.?PBPK model of CC-223 and M1 was developed and verified using clinical results. Model based predictions of DDI with ketoconazole were in agreement with observed results enabling prospective predictions of DDIs between CC-223 and CYP3A4 inhibitors.     

Assessing the potential for drug–drug interactions in an accelerated throughput mode

Drug candidates that cause pharmacokinetic drug drug interactions are less likely to become a commercial success. However, rapid, cost-effective, mechanism-based screens are available for the evaluation of the potential of drug candidates to cause drug&ndashdrug interactions. This review describes experimental designs for, and recent progress in, increasing the throughput of these screens.     

An examination of the potential effect of lipids on the first‐pass metabolism of the lipophilic drug anethol trithione

In this study, an examination of the potential effect of lipids on the first‐pass metabolism of anethol trithione (ATT) was investigated. ATT is metabolized rapidly and extensively in liver into 4‐hydroxy‐anethole trithione (ATX), which was confirmed using the rat intestinal perfusion with the mesenteric cannulation model. Male Sprague–Dawley rats were orally administered of the lipid‐based formulations (prepared by medium chain triglycerides (MCT)), the cyclodextrin formulation and the suspension formulation, respectively. For 6.75 mg/kg groups, ATX/ATT area under the plasma concentration‐time curve (AUC) ratio decreased by 87% and 76% after administration of the MCT‐based formulations and the cyclodextrin formulation, when compared with the suspension formulation (p < 0.05), respectively; for 2.25 mg/kg groups, it decreased by 53% in the MCT group when compared with the cyclodextrin group (p < 0.05). The saturation of pre‐system metabolism of ATT was observed after administration of the MCT‐based formulations and the cyclodextrin formulation, likely as a result of enhanced absorption and therefore presentation of higher drug concentrations to liver, when compared with the suspension formulation. A trend toward lower systemic metabolite to parent ratios was evident after administration of the lipid formulations, when compared with the cyclodextrin formulation; however, this was not statistically significant. Further studies on the potential for lipids to inhibit hepatic metabolism are therefore warranted. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:5048–5058, 2011     

Method for predicting the risk of drug–drug interactions involving inhibition of intestinal CYP3A4 and P-glycoprotein

1. To develop a method to predict the risk of drug–drug interactions involving the inhibition of intestinal CYP3A4 or P-glycoprotein, data from clinical drug–drug interaction studies of CYP3A4 and/or P-glycoprotein substrates were analysed. The ratio of inhibitor dose (Dose_i) to inhibition constant (K_i), termed the drug-interaction number, was used to index intestinal drug–drug interaction.

2. From the analysis, it was found that (1) CYP3A4 inhibitors with a drug-interaction number below 2.8?L have a low risk of interacting with substrates which exhibit intestinal first-pass metabolism and those with a drug-interaction number above 9.4?L have a high risk; (2) P-glycoprotein inhibitors with a drug-interaction number below 10.8?L have a low risk of interacting with P-glycoprotein substrates and those with a drug-interaction number above 27.9?L have a high risk; and (3) the drug-interaction number indexes, 2.8?L and 9.4?L for CYP3A4 and 10.8?L and 27.9?L for P-glycoprotein were validated by data from dual CYP3A4/P-glycoprotein substrates.

3. In conclusion, the drug-interaction number is useful for classifying the risk of drug–drug interactions involving the inhibition of intestinal CYP3A4 and P-glycoprotein. This drug-interaction number-based approach is similar to the method that the US Food and Drug Administration (USFDA) recently proposed in the draft guidance for predicting P-glycoprotein-mediated drug–drug interaction.

     

Recognition and management of potential drug–drug interactions in patients on internal medicine wards

INTRODUCTION: Our aim was to study and possibly improve the clinical management of potential drug-drug interactions (pDDIs) in hospitalized patients by specific interventions. METHODS: During the initial period, inpatients on three medical wards were screened for major and moderate pDDIs using the interaction screening program Pharmavista. During the second period, patients at discharge were screened similarly. After assessment of the detected pDDIs for clinical relevance, written recommendations and/or information about the pDDIs were sent to the treating physicians. Feedback from the physicians and implementation of the recommendations were analyzed. RESULTS: During the initial period, 502 inpatients were exposed to 567 pDDIs, of which 419 (74%) were judged to be clinically relevant. Three hundred and forty-nine substantiated recommendations and 70 simple information leaflets were handed out to the physicians. Eighty percent (278 of 349) of the recommendations were accepted and implemented. During the second period, 792 patients at hospital discharge were exposed to 392 pDDIs, of which 258 (66%) were judged to be clinically relevant. Two hundred and forty-seven substantiated recommendations and 11 simple information leaflets were sent to the physicians. Seventy-three percent (180 of 247) of the recommendations were accepted. At hospital discharge, 47 of 71 interventions recommending checkable medication changes were implemented. One year after hospital discharge, 11 of 13 checked medication changes were still in place. CONCLUSIONS: Clinically relevant pDDIs are common in patients on medical wards, and their management can be influenced by providing substantiated recommendations to physicians. Most changes in medication following such recommendations are still in place 1 year after discharge.     

The metabolism and drug–drug interaction potential of the selective prostacyclin receptor agonist selexipag

1.?The metabolism of selexipag has been studied in vivo in man and the main excreted metabolites were identified. Also, metabolites circulating in human plasma have been structurally identified and quantified.

2.?The main metabolic pathway of selexipag in man is the formation of the active metabolite ACT-333679. Other metabolic pathways include oxidation and dealkylation reactions. All primary metabolites undergo subsequent hydrolysis of the sulphonamide moiety to their corresponding acids. ACT-333679 undergoes conjugation with glucuronic acid and aromatic hydroxylation to P10, the main metabolite detected in human faeces.

3.?The formation of the active metabolite ACT-333679 is catalysed by carboxylesterases, while the oxidation and dealkylation reactions are metabolized by CYP2C8 and CYP3A4. CYP2C8 is the only P450 isoform catalysing the aromatic hydroxylation to P10. CYP2C8 together with CYP3A4 are also involved in the formation of several minor ACT-333679 metabolites. UGT1A3 and UGT2B7 catalyse the glucuronidation of ACT-333679.

4.?The potential of selexipag to inhibit or induce cytochrome P450 enzymes or drug transport proteins was studied in vitro. Selexipag is an inhibitor of CYP2C8 and CYP2C9 and induces CYP3A4 and CYP2C9 in vitro. Also, selexipag inhibits the transporters OATP1B1, OATP1B3, OAT1, OAT3, and BCRP. However, due to its low dose and relatively low unbound exposure, selexipag has a low potential for causing drug–drug interactions.     

Prediction of drug–drug interaction potential using physiologically based pharmacokinetic modeling

The occurrence of drug–drug interactions (DDIs) can significantly affect the safety of a patient, and thus assessing DDI risk is important. Recently, physiologically based pharmacokinetic (PBPK) modeling has been increasingly used to predict DDI potential. Here, we present a PBPK modeling concept and strategy. We also surveyed PBPK-related articles about the prediction of DDI potential in humans published up to October 10, 2017. We identified 107 articles, including 105 drugs that fit our criteria, with a gradual increase in the number of articles per year. Studies on antineoplastic and immunomodulatory drugs (26.7%) contributed the most to published PBPK models, followed by cardiovascular (20.0%) and anti-infective (17.1%) drugs. Models for specific products such as herbal products, therapeutic protein drugs, and antibody–drug conjugates were also described. Most PBPK models were used to simulate cytochrome P450 (CYP)-mediated DDIs (74 drugs, of which 85.1% were CYP3A4-mediated), whereas some focused on transporter-mediated DDIs (15 drugs) or a combination of CYP and transporter-mediated DDIs (16 drugs). Full PBPK, first-order absorption modules and Simcyp^® software were predominantly used for modeling. Recently, DDI predictions associated with genetic polymorphisms, special populations, or both have increased. The 107 published articles reasonably predicted the DDI potentials, but further studies of physiological properties and harmonization of in vitro experimental designs are required to extend the application scope, and improvement of DDI predictions using PBPK modeling will be possible in the future.     

Improvement in the handling of drug–drug interactions

Approximately one in 200 hospitalised patients has a serious adverse drug effect caused by drug–drug interactions (DDIs). Such adverse effects should be avoidable, but current information provided on DDIs is often incomplete and difficult or even impossible to translate into true risk and appropriate tangible action. Clinicians need to know the mean and maximal expected effect of a DDI on clinical endpoints, any dose adjustments required, and how to monitor tolerability and efficacy in patients subject to a DDI. To this end, improved study designs should take the objective of improving treatment explicitly into account, and any existing DDI data should be publicly accessible. Modelling needs to be used more extensively in order to quantitatively predict the effects of DDIs on clinical endpoints in patients and to relate clinical endpoint effects considered as acceptable to respective changes in experimental and clinical studies. Computer-based expert systems will be required to convert such DDI data into recommendations applicable to the individual patient. Therefore, the incorporation of DDIs in a more general procedure for personalisation of drug therapy is desirable.     

Renal drug metabolism in humans: the potential for drug–endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT)

Although knowledge of human renal cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes and their role in xenobiotic and endobiotic metabolism is limited compared with hepatic drug and chemical metabolism, accumulating evidence indicates that human kidney has significant metabolic capacity. Of the drug metabolizing P450s in families 1 to 3, there is definitive evidence for only CYP 2B6 and 3A5 expression in human kidney. CYP 1A1, 1A2, 1B1, 2A6, 2C19, 2D6 and 2E1 are not expressed in human kidney, while data for CYP 2C8, 2C9 and 3A4 expression are equivocal. It is further known that several P450 enzymes involved in the metabolism of arachidonic acid and eicosanoids are expressed in human kidney, CYP 4A11, 4F2, 4F8, 4F11 and 4F12. With the current limited evidence of drug substrates for human renal P450s drug–endobiotic interactions arising from inhibition of renal P450s, particularly effects on arachidonic acid metabolism, appear unlikely. With respect to the UGTs, 1A5, 1A6, 1A7, 1A9, 2B4, 2B7 and 2B17 are expressed in human kidney, whereas UGT 1A1, 1A3, 1A4, 1A8, 1A10, 2B10, 2B11 and 2B15 are not. The most abundantly expressed renal UGTs are 1A9 and 2B7, which play a significant role in the glucuronidation of drugs, arachidonic acid, prostaglandins, leukotrienes and P450 derived arachidonic acid metabolites. Modulation by drug substrates (e.g. NSAIDs) of the intrarenal activity of UGT1A9 and UGT2B7 has the potential to perturb the metabolism of renal mediators including aldosterone, prostaglandins and 20-hydroxyeicosatetraenoic acid, thus disrupting renal homeostasis.     

Evaluation of drug–drug interactions in drug metabolism: Differences and harmonization in guidance/guidelines

The U.S. Drugs and Food Administration (FDA) and the Ministry of Health, Labor and Welfare of Japan (MHLW) issued the drastically revised draft guidance and final guideline on drug-drug interactions (DDI) in 2017 and 2018, respectively. One of the most drastic changes for the evaluation of inhibition potential of drug metabolizing enzymes in the liver using a basic model in these guidance and guideline are represented by the concept to use the unbound maximum concentration in the systemic circulation as the investigational drug concentration instead of the total maximum concentration and the corresponding cutoff values are applied in harmonization with the current DDI guideline of Europe. In this review, the current DDI guidance and guidelines of the three regions are compared and the points which are in common are described. In addition, several issues to be considered and/or clarified such as a criterion for the metabolites to be evaluated as perpetrator drugs, details of in vitro study design etc. are also briefly summarized. Based on further accumulation of data and information, and their continuous international scientific discussion, these issues are expected to be solved to make the current DDI guidance and guidelines be much more harmonized and practically available standards.     

Assessment of liver slices for research on metabolic drug–drug interactions in cattle

1.?Precision-cut liver slices (PCLS) from food-producing animals have not been extensively used to study xenobiotic metabolism, and thus information on this field of research is sparse.

2.?The aims of the present work were to further validate the technique of production and culture of bovine PCLS and to characterize the metabolic interaction between the anthelmintic albendazole (ABZ) and the flavin-monooxygenase (FMO) inhibitor methimazole (MTZ).

3.?Nine steers were used as donors. PCLS were produced and incubated under two methods: a dynamic organ culture (DOC) incubator and a well-plate (WP) system.

4.?Tissue viability, assessed through both structural and functional markers, was preserved throughout 12?h of incubation. ABZ was metabolized to its (+) and (-) albendazole sulfoxide stereoisomers (ABZSO) in bovine PCLS. The interaction between ABZ and MTZ resulted in a reduction (p?p?5.?Both culture systems were suitable for assessing the interaction between ABZ and MTZ.

6.?Overall, the results presented herein show that PCLS are a useful and reliable tool for short-term studies on metabolic drug–drug interactions in the bovine species.     

Recent progress in in vivo phenotyping technologies for better prediction of transporter-mediated drug–drug interactions

Clinical reports on transporter-mediated drug–drug interactions (TP-DDIs) have rapidly accumulated and regulatory guidance/guidelines recommend that sponsors consider performing quantitative prediction of TP-DDI risks in the process of drug development. In vitro experiments for characterizing the function of drug transporters have been established and various parameters such as the inhibition constant (K_i) of drugs and the intrinsic uptake/efflux clearance for a certain transporter can be obtained. However, many reports have indicated large discrepancies between the parameters estimated from in vitro experiments and those rationally explaining drug pharmacokinetics. Thus, it is essential to evaluate directly the function of each transporter isoform in vivo in humans. At present, several transporter substrate drugs and endogenous compounds have been recognized as probe substrates for a specific transporter and transporter function was evaluated by monitoring the plasma and urine concentration of those probes; however, few compounds specifically transported via a single transporter isoform have been found. For monitoring the intraorgan concentration of drugs, positron emission tomography can be a powerful tool and clinical examples for quantification of in vivo transporter function have been published. In this review, novel methodologies for in vivo phenotyping of transporter function are summarized.     

A critical evaluation of clinical decision support for the detection of drug–drug interactions

Introduction: Incorporation of clinical decision support systems (CDSSs) into computerized physician order entry assists prescribers with medication dosing, identification of duplicate therapies, drug-allergy alerts and drug–drug interactions (DDIs). The generation of DDI alerts is one aspect of CDSS that may improve patient safety and reduce adverse drug events.

Areas covered: Currents issues with the generation of DDI alerts, such as alert fatigue, unclear clinical significance and database inconsistencies are a few of the problems that have been identified with DDI alerting. Research has shown that DDI alerting may be improved through the tiering of alerts, generation of patient-specific alert and directing some alerts to clinicians other than physicians. More research in this area, such as how to decrease the variability of database rating systems, improve the identification of clinically significant alerts and increase the patient specificity of the generated DDI alerts, should be conducted.

Expert opinion: DDI knowledgebases need to take into account more patient-specific information. Strategies to avoid alert fatigue, such as DDI tiering and reducing signal:noise ratios, are important areas for future study. End-user participation and clinician feedback should be incorporated in the development of DDI knowledgebases to increase alert compliance.     

Food–drug interactions: effect of capsaicin on the pharmacokinetics of galantamine in rats

1. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide, CAP) is a naturally occurring alkaloid extracted from the fruit of Capsicum plant family. It represents an important ingredient in spicy foods consumed throughout the world. However, little is known about the metabolic interactions between CAP and clinically used drugs.

2. This study attempted to investigate the effect of CAP on the pharmacokinetics of galantamine, a competitive and reversible cholinesterase inhibitor. CAP, dexamethasone or sodium salt of carboxymethyl cellulose (CMC-Na) was given to rats for seven consecutive days and on the seventh day galantamine (10 mg/kg) was administered orally. Dexamethasone was used as a CYP inducer and CMC-Na was used as a vehicle.

3. The results showed that the pretreatment of rats with CAP resulted in a decrease in the AUC_0–∞ of galantamine of about 49.70% (p < 0.01) compared with the control group. After oral administration of galantamine (10 mg/kg), the apparent oral clearance of galantamine was raised by 2.05-fold by pretreatment with CAP (p < 0.05). These results demonstrate that the chronic ingestion of high doses of CAP will decrease the bioavailability of galantamine to a significant extent in rats.

     

Dissolution enhancement of felodipine by amorphous nanodispersions using an amphiphilic polymer: insight into the role of drug–polymer interactions on drug dissolution

Context: Felodipine, a poorly soluble drug, is widely used in the treatment of angina pectoris and hypertension.

Objective: This study aimed at the preparation of amorphous solid dispersion (SD) of felodipine using an amphiphilic polymer, soluplus, for the potential enhancement in solubility of the drug.

Materials and methods: Solid dispersions with varying proportions of drug and soluplus were prepared and the rate and extent of dissolution from SDs was compared with that of the pure drug. FT-IR and ¹H NMR spectroscopic analysis were carried out to examine the formation mechanism of SDs. Various techniques were used for solid state characterization of designed SDs.

Results: Formation of amorphous solid dispersions with particle size in nanometer range indicated suitability of polymer and method used in the preparation. FT-IR and ¹H NMR spectroscopy revealed that soluplus was involved in strong hydrogen bonding with felodipine molecules which resulted in the conversion of crystalline felodipine into amorphous form. Solid dispersion with 1:10 drug/polymer ratio showed more than 90% drug dissolution in 30?min whereas pure felodipine showed less than 19% drug dissolution in 1?h.

Discussion and conclusion: Amorphous SDs of felodipine were prepared using soluplus resulting in substantial enhancement in the rate and extent of dissolution of felodipine.     

Assessment of non-linear combination effect terms for drug–drug interactions

Drugs interact with their targets in different ways. A diversity of modeling approaches exists to describe the combination effects of two drugs. We investigate several combination effect terms (CET) regarding their underlying mechanism based on drug-receptor binding kinetics, empirical and statistical summation principles and indirect response models. A list with properties is provided and the interrelationship of the CETs is analyzed. A method is presented to calculate the optimal drug concentration pair to produce the half-maximal combination effect. This work provides a comprehensive overview of typically applied CETs and should shed light into the question as to which CET is appropriate for application in pharmacokinetic/pharmacodynamic models to describe a specific drug–drug interaction mechanism.     

Polypharmacy and potential drug–drug interactions in emergency department patients in the Caribbean

Background Potential Drug–Drug Interactions (DDI) account for many emergency department visits. Polypharmacy, as well as herbal, over-the-counter (OTC) and combination medication may compound this, but these problems are not well researched in low-and-middle-income countries. Objective To compare the incidence of drug–drug interactions and polypharmacy in older and younger patients attending the Emergency Department (ED). Setting The adult ED of a tertiary teaching hospital in Trinidad. Methods A 4 month cross sectional study was conducted, comparing potential DDI in older and younger patients discharged from the ED, as defined using Micromedex 2.0. Main outcome measure The incidence and severity of DDI and polypharmacy (defined as the use of ≥5 drugs simultaneously) in older and younger patients attending the ED. Results 649 patients were included; 275 (42.3%) were ≥65 years and 381 (58.7%) were female. There were 814 DDIs, of which 6 (.7%) were contraindications and 148 (18.2%) were severe. Polypharmacy was identified in 244 (37.6%) patients. Older patients were more likely to have potential DDI (67.5 vs 48.9%) and polypharmacy (56 vs 24.1%). Herbal products, OTC and combination drugs were present in 8, 36.7 and 22.2% of patients, respectively. On multivariate analysis, polypharmacy and the presence of hypertension and ischaemic heart disease were associated with an increased risk of potential DDI. Conclusion Polypharmacy and potential drug–drug interactions are common in ED patients in the Caribbean. Older patients are particularly at risk, especially as they are more likely to be on multiple medications. The association between herbal medication and polypharmacy needs further investigation. This study indicates the need for a more robust system of drug reconciliation in the Caribbean.