Pharmacokinetic Interactions Research Articles

Final analysis of potential drug-drug interactions between highly purified cannabidiol and anti-seizure medications in an open-label expanded access program.

The aim of this study was to assess potential drug-drug interactions between highly purified cannabidiol (CBD) and anti-seizure medications (ASMs). Our group previously reported that in a sample of adults and children receiving CBD in an open-label expanded access program, there were several ASMs noted to increase in serum levels with increasing doses of CBD. We analyzed if an increased number of observations over time resulted in changes in potential interactions and if potential interactions were associated with time since enrollment, demographics, or the overall rating of adverse effects. In 169 participants (80 adults), with increasing weight-based CBD dose, there were associated increases in serum levels of clobazam and N-desmethylclobazam, free valproate, felbamate, and topiramate in the adult and pediatric arms combined, levetiracetam in the pediatric arm only, and permapanel in the adult arm only. There were no associations noted in these level changes with time since enrollment, biological sex, and adverse events profile scores. This study confirms some previously identified interactions with CBD and identifies other potential pharmacokinetic interactions; however, the clinical significance of these observations is likely minor, and there is no effect of time on these findings.

Tazemetostat synergistically combats multidrug resistance by the unique triple inhibition of ABCB1, ABCC1, and ABCG2 efflux transporters in vitro and ex vivo

ATP-binding cassette (ABC) drug efflux transporters and drug metabolizing enzymes play crucial roles in pharmacokinetic drug-drug interactions and multidrug tumor resistance (MDR). Tazemetostat (EPZ-6438, Tazverik) is a novel epigenetic drug that has been recently approved for the therapy of advanced epithelioid sarcoma and follicular lymphoma. Additionally, this medication is currently being clinically tested to treat several other cancers such as non-small cell lung cancer (NSCLC). This study aimed to investigate the inhibitory effects of tazemetostat on selected ABC transporters/cytochrome P450 3A4 (CYP3A4) enzyme to comprehensively explore its role in MDR. First, our accumulation and molecular docking studies showed that tazemetostat is a unique triple inhibitor of ABCB1, ABCC1, and ABCG2 transporters. In contrast, tazemetostat exhibited only low level of interaction with the CYP3A4 isozyme. Drug combination assays confirmed that tazemetostat is a multipotent MDR modulator able to synergize with various conventional chemotherapeutics in vitro. Subsequent caspase activity assays and microscopic staining of apoptotic nuclei proved that the effective induction of apoptosis is behind the observed synergies. Notably, a potent MDR-modulatory capacity of tazemetostat was recorded in primary ex vivo NSCLC explants generated from patients’ biopsies. On the contrary, its possible position of pharmacokinetic MDR’s victim was excluded in comparative proliferation assays. Finally, tested drug has not been identified as an inducer of resistant phenotype in NSCLC cell lines. In conclusion, we demonstrated that tazemetostat is a unique multispecific chemosensitizer, which has strong potential to overcome limitations seen in the era of traditional MDR modulators.

Tissue re-distribution of budesonide in rats co-administrated with curcumin by ultra performance liquid chromatography-tandem mass spectrometry

Budesonide (BUD), a locally acting glucocorticoid with low side effects, is recommended in several Crohn's disease (CD) drug treatment guidelines as the first choice for early treatment. Nevertheless, the extensive first-pass effect mediated by P-glycoprotein (P-gp) and Cytochrome P450 3A4 (CYP3A4) leads to low bioavailability and limits further applications. Curcumin (CUR), a natural polyphenol derived from turmeric, has been found to influence the in vivo processes of drugs by affecting the activity of P-gp and CYP3A4. However, the pharmacokinetic interactions between BUD and CUR remains elusive, so an ultra high-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS) method was established for the simultaneous determination of BUD and CUR in the tissue. The results showed that the area under the concentration-time curve 0 to time (AUC0→t) of BUD in the colon and kidney increased by approximately 32.35% and 39.03% respectively in the co-administered group compared to the single-drug group, while the small intestine, liver and plasma decreased by 80.03%, 67.34% and 24.34% respectively compared to the single-drug group. Therefore, long-term treatment with CUR can increase the concentration of BUD in the colonic area without increasing its systemic exposure, thus potentially reducing the incidence of side effects.

Pharmacokinetic parameters, safety and drug-drug interactions of mirtazapine and tizanidine, combined in the new original drug Dorsumio®

Objective: to study the pharmacokinetic parameters and safety of Dorsumio® (mirtazapine + tizanidine, extended-release tablets, 15 mg + 6 mg, JSC Valenta Pharm, Russia) taken once by healthy volunteers in comparison with Calixta®, a monocomponent drug (INN: Mirtazapine, filmcoated tablets, 30 mg, Belupo, Drugs and Cosmetics d.d., Republic of Croatia) and Sirdalud® MR (INN: Tizanidine, modified-release capsules, 6 mg, Novartis Pharma AG, Switzerland) with an evaluation of their drug interactions when taken concomitantly or separately.Material and methods. A two-stage, randomized, comparative cross-over study of the pharmacokinetics and safety of the complex drug Dorsumio® was conducted. In the first stage, volunteers alternated between taking one or two tablets of the study drug in two administration periods; in the second stage, subjects alternated between taking the reference monodrugs Calixta® and Sirdalud® MR alone and in a joint combination in three administration periods. A total of 38 volunteers were randomized into the study, of which 14 subjects participated in the first and 24 in the second stage of the study. Quantitative levels of mirtazapine and tizanidine were determined by high-performance liquid chromatography with tandem mass spectrometry. Based on the data obtained, the main pharmacokinetic parameters reflecting the bioavailability of each drug were calculated, and the mutual influence of their combination on pharmacokinetics was also studied. During the study, vital signs and laboratory parameters of the subjects were monitored, and the occurrence of adverse events (AEs) and serious AEs was recorded.Results. A two-fold increase in the dose of the combination drug Dorsumio® resulted in a comparable increase in the pharmacokinetics of the individual drugs. There was no significant reciprocal effect of mirtazapine and tizanidine on their pharmacokinetic parameters. In one of the subjects participating in the second stage of the study, two mild side effects were registered after the joint use of Calixta® and Sirdalud® MR that did not require medical intervention and resolved on their own without health consequences.Conclusion. There were no differences in the safety profile of the combined use of mirtazapine and tizanidine in the form of a free or fixed combination. It was shown that the investigated drug combination had no mutual influence on the pharmacokinetics of the individual components.

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.

Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice.

Goldenseal is a perennial plant native to eastern North America. A recent clinical study reported goldenseal decreased metformin Cmax and area under the blood concentration versus time curve (AUC) by 27% and 23%, respectively, but half-life and renal clearance were unchanged. These observations suggested goldenseal altered processes involved in metformin absorption. The underlying mechanism(s) remain(s) unknown. One mechanism for the decreased metformin systemic exposure is inhibition by goldenseal of intestinal uptake transporters involved in metformin absorption. Goldenseal extract and three goldenseal alkaloids (berberine, (-)-β-hydrastine, hydrastinine) were tested as inhibitors of organic cation transporter (OCT) 3, plasma membrane monoamine transporter (PMAT), and thiamine transporter (THTR) 2 using human embryonic kidney 293 cells overexpressing each transporter. The goldenseal extract, normalized to berberine content, was the strongest inhibitor of each transporter (IC50: 4.9, 13.1, and 5.8 μM for OCT3, PMAT, and THTR2, respectively). A pharmacokinetic study in mice compared the effects of berberine, (-)-β-hydrastine, goldenseal extract, and imatinib (OCT inhibitor) on orally administered metformin. Goldenseal extract and imatinib significantly decreased metformin Cmax by 31% and 25%, respectively, and had no effect on half-life. Berberine and (-)-β-hydrastine had no effect on metformin pharmacokinetics, indicating neither alkaloid alone precipitated the interaction in vivo. A follow-up murine study involving intravenous metformin and oral inhibitors examined the contributions of basolateral enteric/hepatic uptake transporters to the goldenseal-metformin interaction. Goldenseal extract and imatinib had no effect on metformin AUC and half-life, suggesting lack of inhibition of basolateral enteric/hepatic uptake transporters. Results may have implications for patients taking goldenseal with drugs that are substrates for OCT3 and THTR2. SIGNIFICANCE STATEMENT: Goldenseal is used to self-treat respiratory infections and digestive disorders. We investigated potential mechanisms for the clinical pharmacokinetic interaction observed between goldenseal and metformin, specifically inhibition by goldenseal of intestinal uptake transporters (OCT3, PMAT, THTR2) involved in metformin absorption. Goldenseal extract inhibited all three transporters in vitro and decreased metformin systemic exposure in mice. These data may have broader implications for patients co-consuming goldenseal with other drugs that are substrates for these transporters.

An Integrative Approach to Elucidate Mechanisms Underlying the Pharmacokinetic Goldenseal-Midazolam Interaction: Application of In Vitro Assays and Physiologically Based Pharmacokinetic Models to Understand Clinical Observations.

The natural product goldenseal is a clinical inhibitor of CYP3A activity, as evidenced by a 40%-60% increase in midazolam area under the plasma concentration versus time curve (AUC) after coadministration with goldenseal. The predominant goldenseal alkaloids berberine and (-)-β-hydrastine were previously identified as time-dependent CYP3A inhibitors using human liver microsomes. Whether these alkaloids contribute to the clinical interaction, as well as the primary anatomic site (hepatic vs. intestinal) and mode of CYP3A inhibition (reversible vs. time-dependent), remain uncharacterized. The objective of this study was to mechanistically assess the pharmacokinetic goldenseal-midazolam interaction using an integrated in vitro-in vivo-in silico approach. Using human intestinal microsomes, (-)-β-hydrastine was a more potent time-dependent inhibitor of midazolam 1'-hydroxylation than berberine (KI and kinact: 8.48 μM and 0.041 minutes-1, respectively, vs. >250 μM and ∼0.06 minutes-1, respectively). Both the AUC and Cmax of midazolam increased by 40%-60% after acute (single 3-g dose) and chronic (1 g thrice daily × 6 days) goldenseal administration to healthy adults. These increases, coupled with a modest or no increase (≤23%) in half-life, suggested that goldenseal primarily inhibited intestinal CYP3A. A physiologically based pharmacokinetic interaction model incorporating berberine and (-)-β-hydrastine successfully predicted the goldenseal-midazolam interaction to within 20% of that observed after both chronic and acute goldenseal administration. Simulations implicated (-)-β-hydrastine as the major alkaloid precipitating the interaction, primarily via time-dependent inhibition of intestinal CYP3A, after chronic and acute goldenseal exposure. Results highlight the potential interplay between time-dependent and reversible inhibition of intestinal CYP3A as the mechanism underlying natural product-drug interactions, even after acute exposure to the precipitant. SIGNIFICANCE STATEMENT: Natural products can alter the pharmacokinetics of an object drug, potentially resulting in increased off-target effects or decreased efficacy of the drug. The objective of this work was to evaluate fundamental mechanisms underlying the clinically observed goldenseal-midazolam interaction. Results support the use of an integrated approach involving established in vitro assays, clinical evaluation, and physiologically based pharmacokinetic modeling to elucidate the complex interplay between multiple phytoconstituents and various pharmacokinetic processes driving a drug interaction.

In vitro inhibition of human cytochrome P450 enzymes by licoisoflavone B from Glycyrrhiza uralensis Fisch. ex DC.

Glycyrrhiza uralensis Fisch. ex DC, one of the 3 pharmacopeial species of licorice and widely used in dietary supplements, can inhibit certain cytochrome P450 (CYP) enzymes. Thereby, G. uralensis preparations have the potential to cause pharmacokinetic drug interactions when consumed along with prescription medicines. One compound (1.34 mg dry weight) responsible for inhibiting CYP2B6, CYP2C8, and CYP2C9 was isolated using bioactivity-guided fractionation from 250 g dried roots, stolons, and rhizomes. The enzyme kinetics and mechanisms of inhibition were determined using human liver microsomes, recombinant enzymes, and UHPLC-MS/MS-based assays. Identified as licoisoflavone B, this compound displayed reversible inhibition of CYP2C8 with an IC50 value of 7.4 ± 1.1 µM and reversible inhibition of CYP2C9 with an IC50 value of 4.9 ± 0.4 µM. The enzyme kinetics indicated that the mechanism of inhibition was competitive for recombinant CYP2C8, with a Ki value of 7.0 ± 0.7 μM, and mixed-type inhibition for recombinant CYP2C9, with a Ki value of 1.2 ± 0.2 μM. Licoisoflavone B moderately inhibited CYP2B6 through a combination of irreversible and reversible mechanisms with an IC50 value of 16.0 ± 3.9 µM.

Therapeutic advantages of the combined use of closantel and moxidectin in lambs parasitized with resistant gastrointestinal nematodes

The serious widespread development of nematode resistance has motivated the use of combined anthelmintic formulations. However, the advantages/disadvantages of the combined use of anthelmintics require further scientific characterization. The goals of the current trial were a) to characterize the pharmacokinetics of closantel (CLO) and moxidectin (MXD) administered both subcutaneously (sc) and orally either separately or co-administered (CLO + MXD) to lambs; b) to compare the nematodicidal activity of both molecules given individually or co-administered to lambs infected with resistant nematodes. Seventy (70) Corriedale lambs naturally infected with multiple resistant gastrointestinal nematodes were involved in the pharmacokinetic and efficacy trials. The animals were allocated into six groups (n = 10) and treated with either CLO, MXD, or with the CLO + MXD combined formulation by both the oral and sc routes. Additionally, an untreated control group (n = 10) was included for the efficacy trial. The efficacy was estimated by the faecal egg count reduction test (FECRT). Higher systemic exposure of both CLO and MXD was observed after the sc compared to the oral administration in lambs. The combined administration of CLO + MXD did not markedly alter their disposition kinetics. At 13 days post-treatment, the administration of both molecules as a single active principle reached efficacy levels ranging between 80% (MXDoral), 84% (CLOoral), 85% (CLOsc), and 92% (MXDsc). The combined oral and sc treatments reached 99% efficacy. No adverse effects were observed after the combined treatment of CLO + MXD, and their co-administration did not show any adverse pharmacokinetic interaction. The combined effect of CLO + MXD successfully restored the maximum efficacy levels, which were not reached by the individual active ingredients.

Pharmacokinetic Interactions Between Antiseizure and Psychiatric Medications.

Antiseizure medications and drugs for psychiatric diseases are frequently used in combination. In this context, pharmacokinetic interactions between these drugs may occur. The vast majority of these interactions are primarily observed at a metabolic level and result from changes in the activity of the cytochrome P450 (CYP). Carbamazepine, phenytoin, and barbiturates induce the oxidative biotransformation and can consequently reduce the plasma concentrations of tricyclic antidepressants, many typical and atypical antipsychotics and some benzodiazepines. Newer antiseizure medications show a lower potential for clinically relevant interactions with drugs for psychiatric disease. The pharmacokinetics of many antiseizure medications is not influenced by antipsychotics and anxiolytics, while some newer antidepressants, namely fluoxetine, fluvoxamine and viloxazine, may inhibit CYP enzymes leading to increased serum concentrations of some antiseizure medications, including phenytoin and carbamazepine. Clinically relevant pharmacokinetic interactions may be anticipated by knowledge of CYP enzymes involved in the biotransformation of individual medications and of the influence of the specific comedication on the activity of these CYP enzymes. As a general rule, these interactions can be managed by careful evaluation of clinical response and, when indicated, individualized dosage adjustments guided by measurement of drugs serum concentrations, especially if pharmacokinetic interactions may cause any change in seizure control or signs of toxicity. Further studies are required to improve predictions of pharmacokinetic interactions between antiseizure medications and drugs for psychiatric diseases providing practical helps for clinicians in the clinical setting.

Optimization of Therapy in Patients with Epilepsy and Psychiatric Comorbidities: Key Points.

Psychiatric disorder comorbidity in patients with epilepsy (PWE) is very frequent with a mean percentage prevalence of up to 50% and even higher. Such a high frequency suggests that epilepsy and psychiatric disorders might share common pathological pathways. Various aspects contribute in making the matter very complex from a therapeutic point of view. Some antiseizure medications (ASMs), namely valproic acid, carbamazepine, and lamotrigine, have mood-stabilising effects and are routinely used for the treatment of bipolar disorder in patients who do not have epilepsy. Pregabalin and, to a lesser extent, gabapentin, exerts anxiolytic effects. However, several ASMs, in particular levetiracetam, topiramate, and perampanel, may contribute to psychiatric disorders, including depression, aggressive behaviour, and even psychosis. If these ASMs are prescribed, the patient should be monitored closely. A careful selection should be made also with psychotropic drugs. Although most of these can be safely used at therapeutic doses, bupropion, some tricyclic antidepressants, maprotiline, and clozapine may alter seizure threshold and facilitate epileptic seizures. Interactions between ASMs and psychotropic medication may make it difficult to predict individual response. Pharmacokinetic interactions can be assessed with drug monitoring and are consequently much better documented than pharmacodynamic interactions. Another aspect that needs a careful evaluation is patient adherence to treatment. Prevalence of non-adherence in PWE and psychiatric comorbidities is reported to reach values even higher than 70%. A careful evaluation of all these aspects contributes in optimizing therapy with a positive impact on seizure control, psychiatric wellbeing, and quality of life.

Monoamine Oxidase Inhibitors and Clinically Relevant Drug Interactions: A Guide for Preventing Serotonin Toxicity and Hypertensive Reactions

This article describes and clarifies the two significant interactions encountered with monoamine oxidase inhibitors (MAOIs): serotonin toxicity and the tyramine pressor response. This is important because of the amount of inaccurate and misleading information (including in United States Food and Drug Administration-approved product information sheets and online resource and database systems) promulgated over the last few decades, which continues to cause confusion and undue concern. There are few if any clinically relevant CYP450 interactions with psychotropic drugs and no significant pharmacokinetic interactions. Serotonin toxicity is now well understood and only occurs in a problematic form when MAOIs are given in conjunction with serotonin reuptake inhibitors. Major prolonged elevations of blood pressure from tyramine are now less of a concern because of greatly reduced tyramine levels in foods. Therefore, MAOIs are safer and simpler to use in clinical practice than has usually been stated and should be considered earlier in the treatment algorithm for both atypical and melancholic depression. [ Psychiatr Ann . 2023;53(8):353–358.]

Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions: Research Methods and Applications.

Because of the high research and development cost of new drugs, the long development process of new drugs, and the high failure rate at later stages, combining past drugs has gradually become a more economical and attractive alternative. However, the ensuing problem of drug-drug interactions (DDIs) urgently need to be solved, and combination has attracted a lot of attention from pharmaceutical researchers. At present, DDI is often evaluated and investigated from two perspectives: pharmacodynamics and pharmacokinetics. However, in some special cases, DDI cannot be accurately evaluated from a single perspective. Therefore, this review describes and compares the current DDI evaluation methods based on two aspects: pharmacokinetic interaction and pharmacodynamic interaction. The methods summarized in this paper mainly include probe drug cocktail methods, liver microsome and hepatocyte models, static models, physiologically based pharmacokinetic models, machine learning models, in vivo comparative efficacy studies, and in vitro static and dynamic tests. This review aims to serve as a useful guide for interested researchers to promote more scientific accuracy and clinical practical use of DDI studies.

Posaconazole and midostaurin in patients with FLT3-mutated acute myeloid leukemia: Pharmacokinetic interactions and clinical facts in a real life study.

Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin-related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real-life study to evaluate (i) how often concerns around PCZ-midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ-midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p < 0.001 for deviation from guidelines). In the 19 patients managed as per guidelines, PCZ-midostaurin interactions were more remarkable than previously characterized, such that at the end of induction therapy midostaurin minimum plasma concentration (Cmin ) was greater than three times higher than reported; moreover, midostaurin Cmin , maximum plasma concentration, and area under the curve were more than or equal to four times higher with PCZ than micafungin. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin-related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin-treated patient.

Drug-Drug Interaction Between Amlodipine And Clarithromycin In Hypertension Rabbits

This study is the first to examine the possibility of pharmacokinetic interaction in blood circulation using amlodipine and clarithromycin as representatives in hypertension rabbits and identify changes. The current study design required rabbits (n=6) for Pharmacokinetics. In group A, rabbits without treatment were used as control. In group B, were administration of a single dose of amlodipine (0.21mg/kg.BW) for 24 hours. Group C, were administered with a single dose of amlodipine (0.21mg/kg/BW.) and clarithromycin (22 mg/kg/BW.) each 6 hr. for 24 hour. The blood samples were collected from (B and C) groups at time intervals of zero, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, 120, 144 hours and the drug concentrations were estimated using a spectrophotometer and estimated blood pressure using blood pressure cuff with Doppler ultrasound transducer. An increase in C max and AUC in group C (3.52 μg/ml and 130 μg/ml*h) respectively, indicates the improved bioavailability of amlodipine in the presence of clarithromycin compared with group B (2.03 μg/ml and 96.10 μg/ml*h) respectively. Furthermore, reduction in (CL) with an elevation of (Vd) in the presence of clarithromycin (54.94 L/kg/hr. and 4994 L/kg) in group C respectively, compared with group B (74.31 L/kg/hr and 3715 L/kg) respectively. We studied the influence of clarithromycin on the pharmacodynamics of amlodipine in hypertension rabbits. Interaction of amlodipine with multiple doses of clarithromycin produced a high reduction in blood pressure at 9 after administration and the blood pressure continues redaction. In conclusion, the combination of amlodipine with clarithromycin led to the enhancement of the bioavailability of amlodipine by inhibiting the CYP3A4 enzyme leading to producing a hypotension effect with peak plasma concentration effect in hypertension rabbits.

Predicted Pharmacokinetic Interactions Between Hormonal Contraception and Single or Intermittently Dosed Rifampicin.

The scale-up of rifampicin-based prevention regimens is an essential part of the global leprosy strategy. Daily rifampicin may reduce the effectiveness of the oral contraceptive pill (OCP), but little is known about the effects of rifampicin at the less frequent dosing intervals used for leprosy prophylaxis. As many women of reproductive age rely on OCP for family planning, evaluating the interaction with less-than-daily rifampicin regimens would enhance the scalability and acceptability of leprosy prophylaxis. Using a semi-mechanistic pharmacokinetic model of rifampicin induction, we simulated predicted changes in OCP clearance when coadministered with varying rifampicin dosing schedules. Rifampicin given as a single dose (600 or 1200mg) or 600mg every 4weeks was not predicted to result in a clinically relevant interaction with OCP, defined as a >25% increase in clearance. Simulations of daily rifampicin were predicted to increase OCP clearance within the range of observed changes previously reported in the literature. Therefore, our findings suggest that OCP efficacy will be maintained when coadministered with rifampicin-based leprosy prophylaxis regimens of 600mg once, 1200mg once, and 600mg every 4weeks. This work provides reassurance to stakeholders that leprosy prophylaxis can be used with OCP without any additional recommendations for contraception prevention.

Physiologically based pharmacokinetic modeling to assess the drug-drug interactions of anaprazole with clarithromycin and amoxicillin in patients undergoing eradication therapy of H. pylori infection

ObjectiveThis study aimed to assess the pharmacokinetic (PK) interactions of anaprazole, clarithromycin, and amoxicillin using physiologically based pharmacokinetic (PBPK) models. MethodsThe PBPK models for anaprazole, clarithromycin, and amoxicillin were constructed using the GastroPlus™ software (Version 9.7) based on the physicochemical data and PK parameters obtained from literature, then were optimized and validated in healthy subjects to predict the plasma concentration-time profiles of these three drugs and assess the predictive performance of each model. According to the analysis of the properties of each drug, the developed and validated models were applied to evaluate potential drug-drug interactions (DDIs) of anaprazole, clarithromycin, and amoxicillin. ResultsThe developed PBPK models properly described the pharmacokinetics of anaprazole, clarithromycin, and amoxicillin well, and all predicted PK parameters (Cmax,ss, AUC0-τ,ss) ratios were within 2.0-fold of the observed values. Furthermore, the application of these models to predict the anaprazole-clarithromycin and anaprazole-amoxicillin DDIs demonstrates their good performance, with the predicted DDI Cmax,ss ratios and DDI AUC0-τ,ss ratios within 1.25-fold of the observed values, and all predicted DDI Cmax,ss, and AUC0-τ,ss ratios within 2.0-fold. The simulated results show no need to adjust the dosage when co-administered with anaprazole in patients undergoing eradication therapy of H. pylori infection since the dose remained in the therapeutic range. ConclusionThe whole-body PBPK models of anaprazole, clarithromycin, and amoxicillin were built and qualified, which can predict DDIs that are mediated by gastric pH change and inhibition of metabolic enzymes, providing a mechanistic understanding of the DDIs observed in the clinic of clarithromycin, amoxicillin with anaprazole.

Potential pharmacokinetic interactions with concurrent use of herbal medicines and a ritonavir-boosted COVID-19 protease inhibitor in low and middle-income countries.

The COVID-19 pandemic sparked the development of novel anti-viral drugs that have shown to be effective in reducing both fatality and hospitalization rates in patients with elevated risk for COVID-19 related morbidity or mortality. Currently, nirmatrelvir/ritonavir (Paxlovid™) fixed-dose combination is recommended by the World Health Organization for treatment of COVID-19. The ritonavir component is an inhibitor of cytochrome P450 (CYP) 3A, which is used in this combination to achieve needed therapeutic concentrations of nirmatrelvir. Because of the critical pharmacokinetic effect of this mechanism of action for Paxlovid™, co-administration with needed medications that inhibit or induce CYP3A is contraindicated, reflecting concern for interactions with the potential to alter the efficacy or safety of co-administered drugs that are also metabolized by CYP3A. Some herbal medicines are known to interact with drug metabolizing enzymes and transporters, including but not limited to inhibition or induction of CYP3A and P-glycoprotein. As access to these COVID-19 medications has increased in low- and middle-income countries (LMICs), understanding the potential for herb-drug interactions within these regions is important. Many studies have evaluated the utility of herbal medicines for COVID-19 treatments, yet information on potential herb-drug interactions involving Paxlovid™, specifically with herbal medicines commonly used in LMICs, is lacking. This review presents data on regionally-relevant herbal medicine use (particularly those promoted as treatments for COVID-19) and mechanism of action data on herbal medicines to highlight the potential for herbal medicine interaction Herb-drug interaction mediated by ritonavir-boosted antiviral protease inhibitors This work highlights potential areas for future experimental studies and data collection, identifies herbal medicines for inclusion in future listings of regionally diverse potential HDIs and underscores areas for LMIC-focused provider-patient communication. This overview is presented to support governments and health protection entities as they prepare for an increase of availability and use of Paxlovid™.

Pharmacokinetic and pharmacodynamic interaction of DWP16001, a sodium-glucose cotransporter-2 inhibitor, with phentermine in healthy subjects

ABSTRACT Background DWP16001, a sodium-glucose cotransporter-2 inhibitor, has shown promise for improving blood glucose control and facilitating weight loss. Co-administration with phentermine could enhance these effects. So, we aimed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions of DWP16001 and phentermine. Methods We conducted a randomized, open-label, 3-treatment, 6-sequence, 3-period crossover study involving 24 healthy adults. Participants received either DWP16001 (2 mg), phentermine (37.5 mg), or a combination of both once daily for 7 days. Blood samples, urine samples, and body weights were collected to evaluate the PK and PD. Results The PK of the combination was found to be similar to that of the monotherapy. The geometric mean ratio (GMR) of Cmax,ss, and AUCtau,ss were 0.98 and 1.00, respectively, for DWP16001, and 1.01 and 0.94, respectively, for phentermine. Co-administration did not significantly affect the 24-hour urinary glucose excretion compared to DWP16001 monotherapy, and the GMR was 0.90. Participants tended to experience greater weight loss in the combination therapy group, and all demonstrated good tolerance. Conclusions Our findings indicate that there were no significant interactions during co-administration. These results suggest that the combination of DWP16001 and phentermine may be safe and effective for the treatment of obesity and diabetes. Clinical trial registration NCT05321732

Pharmacokinetic and Pharmacodynamic Interactions Between Henagliflozin, a Novel Selective SGLT-2 Inhibitor, and Warfarin in Healthy Chinese Subjects

PurposeWhile controlling blood glucose, patients with diabetes and abnormal coagulation should be treated with positive anticoagulation because the hypercoagulable state of their blood is the primary cause of macroangiopathy. The goal of this study was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) interactions between henagliflozin, a novel selective sodium-glucose cotransporter 2 inhibitor, and warfarin in healthy subjects. MethodsThis single-center, open-label, single-arm clinical study was conducted in 16 healthy male Chinese subjects. According to the study protocol, the PK properties of henagliflozin 10 mg/d and warfarin 5 mg/d were collected and tabulated in accordance with sampling time. All study drugs were given with once-daily administration. Subjects were monitored for adverse reactions and their severity, outcomes, and relationship to study drug. This influences of warfarin on the PK properties of henagliflozin (Cmax,ss and AUCτ,ss), the effects of henagliflozin on the PK properties of warfarin (Cmax, AUC0–t, and AUC0–∞), and the influences of henagliflozin on the PD properties of warfarin (PTmax, PTAUC, INRmax, and INRAUC) were evaluated. FindingsThe geometric mean ratios (GMRs; 90% CIs) of henagliflozin Cmax,ss and AUCτ,ss were 101.75% (96.11%–107.72%) and 102.21% (100.04%–104.42%), respectively. The GMRs (90% CIs) of S- and R-warfarin Cmax, AUC0–t, and AUC0–∞ were as follows: Cmax, 114.31% (106.30%–122.91%) and 115.09% (109.46%–121.01%), respectively; AUC0–t, 120.15% (116.71%–123.69%) and 119.01% (116.32%–121.76%); and AUC0–∞, 120.81% (117.17%–124.58%) and 121.94% (118.90%–125.05%). The GMRs (90% CIs) of warfarin PTmax and PTAUC were 92.73% (91.25%–94.22%) and 97.42% (96.61%–98.24%). The GMRs (90% CIs) of warfarin INRmax and INRAUC were 92.66% (91.17%–94.17%) and 97.36% (96.52%–98.21%). A total of 32 cases of mild adverse events were reported, and were recovered/resolved. There were no serious adverse events reported. ImplicationsNo significant clinically relevant effects on the PK/PD properties of henagliflozin or warfarin were found with coadministration of the two drugs in these healthy male Chinese subjects. Based on these findings, it is expected that henagliflozin and warfarin can be used in combination without dose adjustment. Chinadrugtrials.org.cn identifier: CTR20190240.