Ticagrelor is contraindicated in combination with cytochrome P450 3A4 and 3A5 enzyme (CYP3A4/5) inducers due to increased clearance, causing diminished antiplatelet effects. The emergent nature of acute coronary syndromes (ACS) may preclude scrutinization of home medications before P2Y12 inhibitor administration. The purpose of this case series is to establish the temporal impact of CYP3A4/5 enzyme induction on ticagrelor\'s pharmacodynamic effect by utilizing VerifyNow platelet aggregation studies. This was a retrospective case series of three patients who were taking a CYP3A4/5-inducing medication and loaded with ticagrelor for ACS. The duration of ticagrelor\'s antiplatelet effect was dramatically shortened in the presence of background CYP3A4/5 induction. The offset of antiplatelet effect, defined by platelet reactivity units (PRU), was 10-24 hours in the presence of CYP3A4/5 enzyme induction compared to the anticipated 36-48 hours. This was consistent across CYP3A4/5-inducing medications including carbamazepine, phenobarbital, and phenytoin. This study demonstrates rapid return of platelet function after a ticagrelor loading dose in the presence of CYP3A4/5-inducing medications. Monitoring of PRU every 6-12 hours with subsequent loading with clopidogrel or prasugrel should be considered. Larger scale studies are warranted to confirm these results.

BACKGROUND: Despite evidence demonstrating the effectiveness of aprepitant for chemotherapy-induced nausea and vomiting (CINV), its use in stem cell transplant settings across Canada is not standard. While pharmacokinetic data exists, the clinical significance of cytochrome P450 3A4 (CYP 3A4) inhibition of cyclophosphamide by aprepitant is unclear. Reduced activation of cyclophosphamide may reduce the effectiveness of dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP).
OBJECTIVE: To compare response rates to DICEP in patients with Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) in the presence and absence of aprepitant.
METHODS: A retrospective review of patients who received full-dose DICEP for relapsed/refractory HL or DLBCL between June 1995 and September 2018 at the Foothills Medical Centre (FMC) in Calgary, Alberta, Canada was conducted. Descriptive statistics were used to assess response rate, as defined by the 2007 International Working Group response criteria.
RESULTS: Of the 218 patients included in this study, 87.6% of patients in the control group and 88.5% of patients in the aprepitant group responded to DICEP (difference 0.025 [95% CI, -0.066 to 0.114], p = 0.827). Univariate analyses for age, sex, type of cancer, stage of cancer, number of prior relapses, and relapse status were not significant. No significant differences were observed for secondary outcomes.
CONCLUSIONS: Response rates to DICEP in relapsed/refractory HL and DLBCL patients were similar regardless of aprepitant use. Considering these results and the effectiveness of aprepitant in CINV, its addition to standard antiemetic therapy in patients receiving DICEP should be given strong consideration in the transplant setting.

UNASSIGNED: Cotrimoxazole, a commonly prescribed antibiotic, has substantial resistance, especially in Indonesia, with its uropathogenic resistance reaching 67% in 2017. Although cotrimoxazole has been suggested to be co-administered with lactoferrin to enhance its antibacterial effectiveness and this practice has been widely adopted since the Covid-19 pandemic, the impact of lactoferrin on the pharmacokinetics of cotrimoxazole remains relatively unknown. This study aims to conduct a preliminary clinical investigation into the impact of lactoferrin supplementation on the pharmacokinetics of cotrimoxazole, focusing on the elimination rate and excretion of unchanged drug in urine.
UNASSIGNED: This study employed a blinded, cross-over, single-dose pharmacokinetics investigation, which included five healthy volunteers as participants. In the initial period, the first group received cotrimoxazole (80 mg trimethoprim and 400 mg sulfamethoxazole) along with a lactoferrin-containing supplement, while the second group only received cotrimoxazole. Subsequently, after a washout period, the conditions were reversed. Urine sampling was conducted at intervals from 0 to 24 hours post-medication, and drug levels in the urine were determined using high-performance liquid chromatography.
UNASSIGNED: The population-based pharmacokinetic analysis revealed that the optimal model was the one-compartment model with first-order elimination and proportional residual error.
UNASSIGNED: The findings show that the administration of lactoferrin-containing supplements did not significantly influence the covariate model and, therefore, did not alter the pharmacokinetics parameter of cotrimoxazole in urine with a single administration, implying that lactoferrin did not cause drug interaction problems when given simultaneously.

In the process of the drug development, studies on the cytochrome P450 (CYP) profiles after its administration provided fundamental information regarding drug interactions with concomitantly administered drugs. Here, we evaluated the influence of the administration of H12-(ADP)-liposomes, a platelet substitute, on the mRNA and protein expression, and metabolic activity of CYPs, with focus on the CYP1A2, CYP2C11 and CYP3A2, in rat liver.At 24 h after administering saline or H12-(ADP)-liposomes (10 mg of lipids/kg), a quantitative RT-PCR and western blot analysis revealed that the mRNA and proteins expression of all of the target hepatic CYP isoforms were not different between the saline and H12-(ADP)-liposome groups. Furthermore, an ex vivo CYP metabolic activity assay showed that hepatic CYP metabolic activities in the H12-(ADP)-liposome group were comparable to the corresponding saline group. On the other hand, the area under the blood concentration-time curve for substitutes for CYP1A2 and CYP2C11 was higher in H12-(ADP)-liposome group than in saline group, but the degree of elevations was negligible levels.At a minimum, based on these results, we conclude that H12-(ADP)-liposomes have no quantitative and qualitative effect on the hepatic CYP isoforms, indicating that the drug interactions of H12-(ADP)-liposomes with CYP-metabolizing drugs would be negligible.

UNASSIGNED: This study evaluated the pharmacokinetic interactions of orally administered chloroquine and metoclopramide.
UNASSIGNED: The study employed a randomized and two-phase cross-over design with 4-week washout plan. Twelve healthy male volunteers were shortlisted according to the set criteria and were administered with metoclopramide 10 mg PO and chloroquine (a total of 1500 mg) at different intervals which were (500 mg at 0, 6, and 24 h). The concentration of chloroquine and metoclopramide in the blood samples was estimated using a validated HPLC-UV technique to affirm the maximum concentration (Cmax), time to reach Cmax (Tmax), and area under the curve (AUC).
UNASSIGNED: Cmax, T1/2, and AUC of metoclopramide were increased up to 20, 10, and 47.8%, respectively, by the concomitantly administering Chloroquine. Chloroquine-treated phase showed increased values of Cmax (ng/ml), AUC (ng.h/ml), and T½ (h), i.e. 41.35 ± 1.61, 504.12 ± 66.25, and 5.72 ± 2.63, as compared to that reference phase i.e. 34.52 ± 4.92, 341.14 ± 112.8, and 5.19 ± 1.14, respectively.
UNASSIGNED: Chloroquine was found to attenuate CYP2D6 activity in healthy Pakistani male volunteers. Hence, patients that are prescribed with metoclopramide or other CYP2D6-substrate drugs require a dose adjustment when administered with chloroquine.

The growing co-consumption of botanical natural products with conventional medications has intensified the need to understand potential effects on drug safety and efficacy. This review delves into the intricacies of intestinal pharmacokinetic interactions between botanical natural products and drugs, such as alterations in drug solubility, permeability, transporter activity, and enzyme-mediated metabolism. It emphasizes the importance of understanding how drug solubility, dissolution, and osmolality interplay with botanical constituents in the gastrointestinal tract, potentially altering drug absorption and systemic exposure. Unlike reviews that focus primarily on enzyme and transporter mechanisms, this article highlights the lesser known but equally important mechanisms of interaction. Applying the Biopharmaceutics Drug Disposition Classification System (BDDCS) can serve as a framework for predicting and understanding these interactions. Through a comprehensive examination of specific botanical natural products such as byakkokaninjinto, green tea catechins, goldenseal, spinach extract, and quercetin, we illustrate the diversity of these interactions and their dependence on the physicochemical properties of the drug and the botanical constituents involved. This understanding is vital for healthcare professionals to effectively anticipate and manage potential natural product-drug interactions, ensuring optimal patient therapeutic outcomes. By exploring these emerging mechanisms, we aim to broaden the scope of natural product-drug interaction research and encourage comprehensive studies to better elucidate complex mechanisms.

The clinical management of malignant tumours is challenging, often leading to severe adverse effects and death. Drug resistance (DR) antagonises the effectiveness of treatments, and increasing drug dosage can worsen the therapeutic index (TI). Current efforts to overcome DR predominantly involve the use of drug combinations, including applying multiple anti-cancerous drugs, employing drug sensitisers, which are chemical agents that enhance pharmacokinetics (PK), including the targeting of cellular pathways and regulating pertinent membrane transporters. While combining multiple compounds may lead to drug-drug interactions (DDI) or polypharmacy effect, the use of drug sensitisers permits rapid attainment of effective treatment dosages at the disease site to prevent early DR and minimise side effects and will reduce the chance of DDI as lower drug doses are required. This review highlights the essential use of TI in evaluating drug dosage for cancer treatment and discusses the lack of a unified standard for TI within the field. Commonly used benefit-risk assessment criteria are summarised, and the critical exploration of the current use of TI in the pharmaceutical industrial sector is included. Specifically, this review leads to the discussion of drug sensitisers to facilitate improved ratios of effective dose to toxic dose directly in humans. The combination of drug and sensitiser molecules might see additional benefits to rekindle those drugs that failed late-stage clinical trials by the removal of detrimental off-target activities through the use of lower drug doses. Drug combinations and employing drug sensitisers are potential means to combat DR. The evolution of drug combinations and polypharmacy on TI are reviewed. Notably, the novel binary weapon approach is introduced as a new opportunity to improve TI. This review emphasises the urgent need for a criterion to systematically evaluate drug safety and efficiency for practical implementation in the field.

Although nirmatrelvir/ritonavir (NMV/r) reportedly increases blood levels of tacrolimus (TAC) due to CYP3A4 inhibition and other factors, reports on the use of NMV/r in combination with tacrolimus hydrate extended-release capsules (TAC-ER) in lung transplant patients are limited. Herein, we present a case with post-lung transplantation of elevated blood trough levels of TAC after concomitant use of NMV/r. A woman in her 60s had undergone lung transplantation. She had coronavirus disease 2019 (COVID-19) and was co-administered NMV/r and TAC-ER, with the trough level controlled at approximately 4 μg/mL. Upon the co-administration of NMV/r and TAC-ER, the patient developed diarrhea and vomiting and was hospitalized. TAC-ER was discontinued on day 6, and TAC level was measured on day 8 and had risen above 100 ng/mL. This level gradually decreased to 17.8 ng/mL on day 11 and 2.4 ng/mL on day 15; therefore, TAC-ER was resumed at 2.5 mg/day. On day 18, the TAC level was 5.2 ng/mL, which was within the target range, and the patient was discharged on day 19. This is the first report of a post-lung transplant patient co-administered TAC-ER with NMV/r, who showed abnormally high blood TAC levels above the detection limit. In patients using TAC-ER after lung transplantation, it may be useful to confirm that the TAC blood level is below the effective therapeutic range before resuming TAC-ER safely.

UNASSIGNED: Voriconazole is primarily metabolized by CYP2C19 and CYP3A4. Drug interactions that affect this pathway can alter its plasma exposures, resulting in untargeted voriconazole concentrations.
UNASSIGNED: In this case report, we describe the case of a 64-year-old man who was treated for non-Hodgkin\'s lymphoma with continuous glucocorticoids co-administrated with voriconazole against invasive pulmonary aspergillosis. A decrease in trough concentration (Cmin) of voriconazole was observed and related with co-administration of dexamethasone in the patient carrying the CYP2C19 *1*2 genotype: voriconazole Cmin/dose ratios of 0.018 (0.1 mg L-1/5.7 mg kg-1 day-1), 0.18 (1 mg L-1/5.7 mg kg-1 day-1), and 0.23 (2 mg L-1/8.6 mg kg-1 day-1) at dexamethasone doses of 20, 12.5, and 2.5 mg, respectively. Sub-therapeutic voriconazole Cmin was associated with high- and moderate-dose dexamethasone (20 and 12.5 mg), leading to failure of antifungal treatment.
UNASSIGNED: The extent of voriconazole-dexamethasone interaction was determined by the dose of dexamethasone and associated with the CYP2C19 *1*2 genotype. Therapeutic drug monitoring of voriconazole is necessary to avoid clinically relevant interactions for optimal antifungal therapy.

BACKGROUND: Statins are widely used in cardiovascular disease (CVD) as a common lipid-lowering drug, while quinolones are widely used for the treatment of infectious diseases. It is common to see CVD in combination with infectious diseases, therefore it is often the case that statins and quinolones are used in combination. Data suggest combinations of statin and quinolone may be associated with potentially life-threatening myopathy, rhabdomyolysis and acute hepatitis. This systematic review aims to characterize data regarding patients affected by the statin-quinolone interaction.
METHODS: The purpose of this systematic review was to collect and evaluate the evidence surrounding statin-quinolone drug interactions and to discuss related risk mitigation strategies. The following databases were searched: PubMed (Medline), Embase, Scopus, and Cochrane Library. The systematic electronic literature search was conducted with the following search terms. In this study, three types of search terms were used: statins-related terms, quinolones-related terms, and drug interactions-related terms.
RESULTS: There were 16 case reports that met the criteria for qualitative analysis. Patients were involved in the following adverse reactions: rhabdomyolysis (n = 12), acute hepatitis (n = 1), muscle weakness (n = 1), hip tendinopathy (n = 1), or myopathy (n = 1). In the included literature, patients vary in the dose and type of statins they take, including simvastatin (n = 10) at a dose range of 20-80 mg/d and atorvastatin (n = 4) at a dose of 80 mg/d. There were 2 patients with unspecified statin doses, separately using simvastatin and atorvastatin. The quinolones in combination were ciprofloxacin (n = 9) at a dose range of 800-1500 mg/d, levofloxacin (n = 6) at a dose range of 250-1000 mg/d, and norfloxacin (n = 1) in an unspecified dose range. 81% of the case patients were over 60 years of age, and about 1/3 had kidney-related diseases such as diabetic nephropathy, post-transplantation, and severe glomerulonephritis. Nearly two-third of the patients were on concomitant cytochrome P450 3A4 (CYP3A4) inhibitors, P-glycoprotein (P-gp) inhibitors, or organic anion transporting polypeptide 1B1 (OATP1B1) inhibitors.
CONCLUSIONS: Patients treated with statin-quinolone combination should be monitored more closely for changes in aspartate aminotransferase or creatine kinase (CK) levels, and muscle symptoms, especially in patients with ciprofloxacin or levofloxacin, with simvastatin and high-dose atorvastatin, over 60 years of age, with kidney-related diseases, and on concomitant CYP3A4 inhibitors.