Model-informed assessment of ethnic sensitivity and dosage justification for Asian populations in the global clinical development and use of cladribine tablets.

Cladribine tablets have been approved in many countries for the treatment of patients with various forms of relapsing multiple sclerosis (MS). Cladribine has a unique pharmacokinetic/pharmacodynamic (PK/PD) profile with a short elimination half-life (~ 1 day) relative to a prolonged PD effect on specific immune cells (most notably a reversible reduction in B and T lymphocyte counts). This results in a short dosing schedule (up to 20 days over 2 years of treatment) to sustain efficacy for at least another 2 years. Global clinical studies were conducted primarily in White patients, in part due to the distinctly higher prevalence of MS in White patients. Given the very low prevalence in Asian countries, MS is considered as a rare disease there. In spite of the limited participation of Asian patients, to demonstrate favorable benefit/risk profile in the treatment of MS demanded application of a Totality of Evidence approach to assess ethnic sensitivity for informing regulatory filings in Asian countries and supporting clinical use of cladribine in Asian patients. Population PD modeling and simulation of treatment-related reduction in absolute lymphocyte count, as a mechanism-related biomarker of drug effect, confirmed consistent PDs in Asian and non-Asian patients with MS, supporting absence of ethnic sensitivity and a common dosage across populations. Through this example, we demonstrate the value of holistic integration of all available data using a model-informed drug development (MIDD) framework and a Totality of Evidence mindset to evaluate ethnic sensitivity in support of Asia-inclusive development and use of the drug across populations.

Effect of itraconazole, food, and ethnic origin on the pharmacokinetics of ivosidenib in healthy subjects.

PURPOSE: To assess the effect of ethnicity, food, and itraconazole (strong CYP3A4 inhibitor) on the pharmacokinetics of ivosidenib after single oral doses in healthy subjects. METHODS: Three phase 1 open-label studies were performed. Study 1: Japanese and Caucasian subjects received single doses of 250, 500, or 1000 mg ivosidenib (NCT03071770). Part 1 of study 2 (a two-period crossover study): subjects received 500 mg ivosidenib after either an overnight fast or a high-fat meal. Subjects received 1000 mg ivosidenib after an overnight fast in the single period of part 2 (NCT02579707). Study 3: in period 1, subjects received 250 mg ivosidenib; then, in period 2, subjects received oral itraconazole (200 mg once daily) on days 1-18, plus 250 mg ivosidenib on day 5 (NCT02831972). RESULTS: Ivosidenib was well tolerated in all three studies. Study 1: pharmacokinetic profiles were generally comparable, although AUC and Cmax were slightly lower in Japanese subjects than in Caucasian subjects, by ~ 30 and 17%, respectively. Study 2: AUC increased by ~ 25% and Cmax by ~ 98%, when ivosidenib was administered with a high-fat meal compared with a fasted state. Study 3: co-administration of itraconazole increased ivosidenib AUC by 169% (90% CI 145-195) but had no effect on ivosidenib Cmax. CONCLUSIONS: No ivosidenib dose adjustment is deemed necessary for Japanese subjects. High-fat meals should be avoided when ivosidenib is taken with food. When co-administered with strong CYP3A4 inhibitors, monitoring for QT interval prolongation (a previously defined adverse event of interest) is recommended and an ivosidenib dose interruption or reduction may be considered. CLINICALTRIALS.GOV : NCT03071770, NCT02579707, and NCT02831972.

Organic Ion Transporters and Statin Drug Interactions.

PURPOSE OF REVIEW: Statin drug-drug interactions (DDIs) are both troublesome to patients as well as costly to medical resources. The ability to predict and avoid these events could lead to improved outcomes as well as patient satisfaction. This review will explore efforts to better understand and predict these interactions specifically related to one drug transport system, the organic anion-transporting polypeptides (OATPs) specifically OATP1B1 and OATP1B3. RECENT FINDINGS: Since the publication of the discovery of OATPs, there have been various pharmacokinetic models that have been proposed to explain the variation in pharmacokinetic and clinical effects related to the OATPs. The effects in transport activity appear to be partially related to the individual polymorphisms studied. Drug-drug interactions can occur when other drugs compete for the metabolic site on the OATPs. Various medications are identified as substrates and/or inhibitors of the OATPs, thereby complicating the ability to fully predict the impact on levels and effects. All of the models reviewed claim successes but show limited clinical utility. There are specific populations that have been identified, predominately various Asian descendants that require lower doses of statins to avoid adverse events. The concept of attributing these actions to the OATPs has been explored, but current models cannot accurately predict statin blood levels or elimination constants. The current research only points to the differences in the human genome and the single-nucleotide polymorphisms that exist between us. Based upon the currently available studies, there is beginning to be a glimmer in the understanding how different populations respond to statin transport and elimination. Additionally and unfortunately, there are other enzymes to be studied to better predict patient differences. Clearly, there has been much work completed, yet many more questions require answering to better understand these transport proteins.

LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma.

BACKGROUND: Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs. METHODS: We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib. RESULTS: The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet. CONCLUSIONS: The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.

Predictors of warfarin dose requirements in South African patients attending an anticoagulation clinic.

INTRODUCTION: Warfarin is the most common oral anticoagulant for the treatment and prevention of thromboembolic disease. However, it has a wide interpatient variability in dose requirements due to various genetic and clinical factors. MATERIALS AND METHODS: This study investigated the effect of clinical and genetic factors on the variability of warfarin dose requirements in 147 South African patients (81 white and 66 black). The study was performed at a University Hospital Anticoagulation Clinic managed by nursing sisters at the Charlotte Maxeke Johannesburg Academic Hospital. RESULTS: The most common indication for anticoagulation was atrial fibrillation (n = 55, 37.4%). The mean warfarin dose was significantly higher in black patients as compared to white patients (5.4 ± 2.9 mg/day and 3.8 ± 2.1 mg/day, respectively; P < 0.001). Older age was significantly associated with a lower maintenance warfarin dose (P < 0.001). Drugs which decreased the international normalized ratio (INR) were significantly associated with a higher maintenance warfarin dose of 6.4 ± 3.4 mg/day (P < 0.034). In contrast, there was no significant difference in warfarin dosage requirements in the presence of CYP2C9 and VKORC1 variant alleles (P > 0.05). Patients, however, homozygous for CYP2C9 *1,*3, and VKORC1 required less than 5 mg/day of warfarin to maintain the INR within the therapeutic range. CONCLUSION: In conclusion, this study indicates that clinical characteristics including; age, ethnic group, and drugs which decrease the INR might help to predict better dose requirements in this population group and thereby reduce the risk of bleeding and thrombotic complications.

Bridging cross-cultural gaps: monitoring herbal use during chemotherapy in patients referred to integrative medicine consultation in Israel.

INTRODUCTION: The high prevalence of the use of traditional herbs among patients with cancer is a cause for concern with regard to potentially adverse interactions with conventional oncology treatments. In this study, we explore herbal use among patients with cancer in northern Israel who are referred by their health care providers to complementary and traditional medicine (CTM) consultations provided to them within the conventional oncology department. The study's objectives were to identify which herbs patients use and to examine the scope of current research on the efficacy and safety regarding the identified herbs. PATIENTS AND METHODS: Herbal use by patients receiving oncology care was assessed prospectively from July 2009 to July 2012 by integrative physicians (IPs) trained in herbal medicine. Historical, ethnobotanical, basic research, and clinical data regarding the identified herbs were explored by using a keyword search in PubMed and Middle Eastern ethnohistorical literature. RESULTS: Disclosure of herbal use was reported by 154 of the 305 patients (50.5 %) interviewed by IPs. The use of 85 single herbs and 30 different herbal formulas was documented during the initial or follow-up IP assessments. Patients reported 14 quality of life-associated indications for herbal use. The ten most prevalent herbs displaying in vitro/in vivo anticancer activity and nine other herbs were preliminarily assessed concerning potential risks, safety, and interaction with chemotherapy. CONCLUSIONS: Herbal use by patients with cancer in northern Israel is widespread and calls for further study in order to address issues of safety and effectiveness. We recommend constructing a multinational and multidisciplinary team of researchers with ethnopharmacological and clinical expertise that will explore the use of herbs among patients with cancer in a cross-cultural perspective attuned with patients' affinity to traditional herbal medicine.

Pharmacokinetics, safety, and tolerability of ascending doses of sublingual fentanyl, with and without naltrexone, in Japanese subjects.

This open-label, nonrandomized study assessed single and repeat ascending doses of a new sublingual fentanyl (SLF) formulation in 48 healthy Japanese opiate-naïve subjects (47 completed). Subjects received single-dose SLF 100, 200, 400, or 800 µg followed by 13 doses 6 hourly, at their dose level. Subjects taking repeat-dose 400 and 800 µg were pretreated with naltrexone in order to block opiate-receptor-mediated effects on respiration, monitored by pulse oximetry and transcutaneous pco(2). Sublingual fentanyl was rapidly and consistently absorbed. After single doses, median t(first) was 0.08 to 0.25 hours and t(max) 0.50 to 1.00 hours. After repeat dosing, median t(max) (t(max,ss)) was 0.50 to 2.00 hours. Plasma concentrations were dose proportional both after single and repeat dosing, and naltrexone appeared to have no effect on SLF pharmacokinetics. Plasma fentanyl reached steady state within the 72-hour dosing period and accumulation was approximately 2-fold. After single doses, effects on respiratory variables were evident after the 400-µg and 800-µg doses. Transcutaneous pco(2) was not helpful in detecting respiratory depression. Thus, SLF yielded rapid absorption of fentanyl and dose-proportional plasma concentrations that, for 400 µg and 800 µg, were within the typical analgesic range. Respiratory depression in these opioid-naïve volunteers was manageable with simple clinical measures.

Alterações sistêmicas e consumo de fármacos entre usuários das clínicas de Odontologia, Belo Horizonte, 2004

Considerando a importância da avaliação de sistemas para o atendimento odontológico, avaliou-se a prevalência de alteações sistêmicas e da utilização de medicamentos entre usuários das clínicas odontológicas de um curso de Odontologia em Belo Horizonte, Minas Gerais e os fatores associados à utilização de fármacos, 2004...

Interações medicamentosas como causa de eventos adversos em idosos: os inibidores da enzima conversora da angiotensina (IECA) / Drug interactions as a cause of adverse events in the elderly: the angiotensin-converting enzyme inhibitors

Devido à idade avançada os idosos freqüentemente apresentam múltiplas patologias e necessitam fazer uso de mais de um medicamento, estando assim, sujeitos a interações medicamentosas indesejadas que podem resultar em eventos adversos. O trabalho tem como objetivo estudar as potenciais interações medicamentosas devidas ao uso simultâneo de dois ou mais fármacos em idosos. (...)