Potential Pharmacokinetic Drug-drug Interactions Research Articles

Drug–drug interactions between sucroferric oxyhydroxide and losartan, furosemide, omeprazole, digoxin and warfarin in healthy subjects

BackgroundThe novel iron-based phosphate binder sucroferric oxyhydroxide is being investigated for the treatment of hyperphosphatemia. Patients with chronic kidney disease often have multiple comorbidities that may necessitate the daily use of several types of medication. Therefore, the potential pharmacokinetic drug–drug interactions between sucroferric oxyhydroxide and selected drugs commonly taken by dialysis patients were investigated.MethodsFive Phase I, single-center, open-label, randomized, three-period crossover studies in healthy volunteers investigated the effect of a single dose of sucroferric oxyhydroxide 1 g (based on iron content) on the pharmacokinetics of losartan 100 mg, furosemide 40 mg, omeprazole 40 mg, digoxin 0.5 mg and warfarin 10 mg. Pharmacokinetic parameters [including area under the plasma concentration–time curve (AUC) from time 0 extrapolated to infinite time (AUC0–∞) and from 0 to 24 h (AUC0–24)] for these drugs were determined: alone in the presence of food; with sucroferric oxyhydroxide in the presence of food; 2 h after food and sucroferric oxyhydroxide administration.ResultsSystemic exposure based on AUC0–∞ for all drugs, and AUC0–24 for all drugs except omeprazole (for which AUC 0–8 h was measured), was unaffected to a clinically significant extent by the presence of sucroferric oxyhydroxide, irrespective of whether sucroferric oxyhydroxide was administered with the drug or 2 h earlier.ConclusionsThere is a low risk of drug–drug interactions between sucroferric oxyhydroxide and losartan, furosemide, digoxin and warfarin. There is also a low risk of drug–drug interaction with omeprazole (based on AUC0–∞ values). Therefore, sucroferric oxyhydroxide may be administered concomitantly without the need to adjust the dosage regimens of these drugs.

A phase I clinical and pharmacokinetic study evaluating vinflunine in combination with epirubicin as first-line treatment in metastatic breast cancer

Vinflunine (VFL) is a bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with epirubicin (EPR) to establish the recommended dose (RD), to evaluate the safety and efficacy profiles and to investigate potential pharmacokinetic (PK) drug-drug interaction (DDI). Two schedules (day 1 every 3 weeks; days 1 and 8 every 3 weeks) were investigated as first-line chemotherapy of metastatic breast cancer patient. PK DDI was evaluated through population PK approaches. Thirty-nine patients received a total of 197 cycles of the VFL-EPR combination (median 6). The RDs were VFL 250 mg/m(2) + EPR 75 mg/m(2) every 3 weeks for schedule 1 and VFL 170 mg/m(2) + EPR 35 mg/m(2) every 3 weeks for schedule 2. The PK analysis demonstrated no clinically relevant mutual DDI between VFL and EPR. The main dose-limiting toxicity was neutropenia. The most frequent non-haematological adverse events were nausea, fatigue, constipation, vomiting, anorexia and stomatitis. Objective response rate was achieved in 45.9 % of the patients. VFL-EPR combination is feasible with manageable toxicity. The antitumour activity was promising and supports further evaluation.

Absence of pharmacokinetic drug–drug interaction of pertuzumab with trastuzumab and docetaxel

Pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel. In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer.

A phase 1 study of vinflunine in combination with trastuzumab for the treatment for HER2-positive metastatic breast cancer

To determine the recommended dose (RD) of vinflunine in combination with trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and to investigate potential pharmacokinetic (PK) interactions. In the first part of the study, two dose levels of vinflunine given every 3 weeks were explored (280 and 320 mg/m(2)) combined with trastuzumab (4 mg/kg loading dose and 2 mg/kg weekly). For each level of dose, six patients were enrolled to determine the RD for phase 2 studies (RP2S). In the second part of the study, 18 additional patients at RP2S have been evaluated to confirm safety and investigate preliminary antitumor activity. The RD was 320 mg/m(2) according to the dose escalation plan. Eleven of 15 additional patients who received this dose experienced dose-limiting toxicities, leading to a reduction in the RD to 280 mg/m(2). When compared to prior trials when vinflunine was used as a single agent, neither vinflunine total blood clearance nor trastuzumab serum concentrations were modified when the drugs were combined. All patients were evaluable, and the overall response rate was 73.3 % (95 % CI 54.1-87.7). The median progression-free survival was 11.3 months (95 % CI 9.4-21.0). At the dose of 280 mg/m(2), grade 3-4 neutropenia were seen in 4 patients (44.4 %) without febrile neutropenia. Non-hematologic grade 4 toxicities were not reported while grade 3 peripheral sensory neuropathy concerned 2 patients (22.2 %). The RD of vinflunine in combination with the standard regimen of trastuzumab is 280 mg/m(2) every 3 weeks. No mutual PK drug-drug interaction was seen. This regimen appears to be active with a favorable safety profile. Its role in HER2-positive MBC treatment needs to be defined in prospective comparative clinical trials.

Exposure to Potential CYP450 Pharmacokinetic Drug–Drug Interactions among Osteoarthritis Patients: Incremental Risk of Multiple Prescriptions

Patients taking more than one drug metabolized through the cytochrome P450 (CYP450) enzyme system experience a drug-drug exposure (DDE), which puts them at risk for a potential pharmacokinetic drug-drug interaction (DDI), defined as two or more drugs interacting in such a way that the effectiveness and/or toxicity of one or all drugs are changed. Any patient subjected to a DDE is at risk for a potentially serious DDI, the epidemiology of which has not been thoroughly studied. Many drugs are metabolized primarily via the CYP450 enzyme system, including certain opioids used to manage moderate to severe chronic pain. We conducted a retrospective analysis of a large commercial claims database and a Medicare database to assess the prevalence of DDEs among patients with osteoarthritis taking CYP450-metabolized opioids. The overall prevalence of DDEs in this population was 26%, with females more likely to experience DDEs than males (28.4% vs. 21.0%, respectively). The number of unique concurrent prescriptions at baseline, gender, age, and Charlson Comorbidity Index were statistically significant predictors of DDEs (P < 0.05). This study challenged previous assumptions about DDEs in that advanced age was not positively associated with the risk of DDE. However, the number of prescriptions the patient received in the 90-day window prior to the index date was a risk factor. For patients taking at least two medications in the 90-day period prior to the index date, every additional prescription taken increased their risk for a DDE during the observation period by 138% (on average). The risk of DDE during the study period was threefold greater for patients with one medication in the 90-day period before index date compared with similar patients with no prescriptions in that same period before the index date. DDEs are more common than may be generally believed in patients with osteoarthritis, regardless of age, and can occur even in patients taking few medications. When selecting an opioid analgesic to treat osteoarthritis, physicians should consider the potential for exposure of these patients to drugs that could interact unfavorably.

Inhibitory effects of curcumenol on human liver cytochrome P450 enzymes

Curcumenol, one of the major components of Zedoary turmeric oil, has been widely used to treat cancer and inflammation. As an antibiotic or anticancer drug, curcumenol is highly likely to be used in combination with various synthetic drugs in most cases, thus it is necessary to evaluate potential pharmacokinetic drug-drug interactions induced by curcumenol. In this study, the inhibitory effects of curcumenol on seven CYP isoforms were investigated, and the results demonstrated that only CYP3A4 was strongly inhibited (IC(50) = 12.6 +/- 1.3 microM). Kinetic analysis showed the inhibition type was competitive with K(i) value of 10.8 microM. Time- and NADPH-dependent inhibitions were also investigated to show curcumenol is not a mechanism-based inhibitor. Employing these in vitro data and maximum plasma concentration of curcumenol in human predicted from beagle dog's in vivo pharmacokinetic data, the change in AUC of victim drugs was predicted to be 0.4%, which suggested that curcumenol may be safely used without inducing metabolic drug-drug interaction through P450 inhibition. Nevertheless, due to the limited pharmacokinetic data available for curcumenol in humans, it is still not possible to evaluate its potential clinical effects on human patients from in vitro data. Thus, the magnitude of drug-drug interaction (DDI) induced by curcumenol warrants further investigation.

Coadministration of Pioglitazone or Glyburide and Alogliptin: Pharmacokinetic Drug Interaction Assessment in Healthy Participants

Alogliptin is a dipeptidyl peptidase-4 inhibitor under investigation for treatment of patients with type 2 diabetes mellitus. Potential pharmacokinetic (PK) drug-drug interactions of alogliptin with pioglitazone or glyburide were evaluated in healthy adults. In a randomized, 6-sequence, 3-period crossover study (study I), participants (n = 30 enrolled; n = 27 completed) received monotherapy with pioglitazone 45 mg once daily (qd), alogliptin 25 mg qd, or coadministration of the 2 agents. The 12-day treatment periods were separated by a > or =10-day washout interval. In a nonrandomized, single-sequence study (study II), participants (n = 24 completed) received a single 5-mg dose of the sulfonylurea glyburide, alone and after 8 days of dosing with alogliptin 25 mg qd. Sequential samples of blood (both studies) and urine (first study) were obtained for determination of PK parameters for alogliptin, pioglitazone, their metabolites, and glyburide. Minor changes in PK parameters between combination therapy and monotherapy were obtained but not judged to be clinically relevant. The combination treatments were well tolerated, although glyburide frequently caused hypoglycemia. Most adverse events were of mild intensity and occurred with a frequency similar to that with monotherapy. It is concluded that pioglitazone or glyburide can be administered with alogliptin without dose adjustment to any component of the combination therapy.

Antiretroviral and immunosuppressive drug-drug interactions: An update

With the introduction of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV) infection has become a chronic disease with more frequent end-stage organ failures. As a result, the question of transplantation in HIV patients is raised more often. However, some of the HAART regimen medications require elimination or metabolism via the P-glycoprotein (P-gp) and multidrug-resistant protein (MRP) transporters or via the cytochrome P450 enzyme system. Since these transporters and enzymes are also responsible for the clearance of immunosuppressive drugs, drug-drug interactions are likely to occur. Indeed, profound drug-drug interactions between protease inhibitors and immunosuppressive drugs have been observed and they required reductions in drug dosage. In contrast, HAART using nucleoside or nonnucleoside reverse transcriptase inhibitors without the use of protease inhibitors has been shown to produce less significant drug-drug interactions. It is thus crucial to take into account those potential pharmacokinetic and/or pharmacodynamic drug-drug interactions in order to avoid drug toxicity or a lack of efficacy. The aim of this work was to review and synthesize the international literature on this field in order to give practical recommendations on how to manage immunosuppressive drugs in HIV patients who get transplanted and on how to handle HAART therapy in transplant-recipient patients who get infected with HIV.

Potential interaction between acenocoumarol and diclofenac, naproxen and ibuprofen and role of CYP2C9 genotype.

NSAIDs are reported to increase the risk of bleeding in coumarin users. The mechanism underlying this risk is inhibition of platelet aggregation, however a pharmacokinetic mechanism resulting in an increased International Normalised Ratio (INR) was proposed in some case reports in warfarin treated patients. In this retrospective cohort study the influence of diclofenac, naproxen and ibuprofen on the INR of outpatients stabilised on acenocoumarol therapy was investigated. We also determined the role of cytochrome P450 2C9 (CYP2C9) polymorphism on coumarin dosage and INR in NSAID users. The study was carried out at the Groningen Outpatient Thrombosis Service. A retrospective cohort study among patients who received both acenocoumarol and one of the NSAIDs under study was performed. Patients whose INR rose above the upper level of the therapeutic range (INR above 3.5 or 4.0) after an NSAID under study was added to the acenocoumarol therapy, were compared with patients who did not show such an elevation. A two-sample t-test (average acenocoumarol dosage, age), and chi-square tests (sex, therapeutic range, type of NSAID) were used to test for differences. Genotyping was carried out by analysing blood samples for the relevant CYP2C9 alleles. The study population consisted of 112 patients on stable acenocoumarol therapy, of which 52 (46%) showed an elevation of the INR above the desired therapeutic level (INR 3.5 and 4.0 respectively) after the start of an NSAID under study. In 12 patients, the INR increased above 6. The INR of the other 60 patients (54%) remained constant after the start of one of the NSAIDs under study. There were no statistically significant differences between patients with increased INR and patients without increased INR with regard to age, sex, therapeutic range and average acenocoumarol dosage. Eighty patients, of whom 36 showed an increased INR as a result of a potential acenocoumarol-NSAID drug interaction, were included in the genotyping study. No association between CYP2C9 genotype and an increased INR as a result of the drug-drug interaction was found. In nearly half of a cohort of elderly patients, the INR increased beyond the therapeutic range (INR 3.5 or 4.0) as a result of a potential pharmacokinetic drug-drug interaction between acenocoumarol and diclofenac, naproxen and ibuprofen. The average increase in INR was between 1 and 4. Polymorphism of CYP2C9 does not seem to be a relevant risk factor for the NSAID-acenocoumarol interaction.