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Safety of the Geneva Cocktail, a Cytochrome P450 and P-Glycoprotein Phenotyping Cocktail, in Healthy Volunteers from Three Different Geographic Origins.
Rollason, V, Mouterde, M, Daali, Y, Čížková, M, Priehodová, E, Kulichová, I, Posová, H, Petanová, J, Mulugeta, A, Makonnen, E, et al
Drug safety. 2020;(11):1181-1189
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Abstract
UNLABELLED INTRODUCTION AND OBJECTIVE Cytochrome P450 enzymes are the major drug-metabolizing enzymes in humans and the importance of drug transport proteins, in particular P-glycoprotein, in the variability of drug response has also been highlighted. Activity of cytochrome P450 enzymes and P-glycoprotein can vary widely between individuals and genotyping and/or phenotyping can help assess their activity. Several phenotyping cocktails have been developed. The Geneva cocktail is composed of a specific probe for six different cytochrome P450 enzymes and one for P-glycoprotein and was used in the context of a research aiming at exploring genotypes and phenotypes in distinct human populations (NCT02789527). The aim of the present study is to solely report the safety results of the Geneva cocktail in the healthy volunteers of these populations. MATERIALS AND METHODS The Geneva cocktail is composed of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, and fexofenadine. The volunteers fasted and avoided drinking caffeine-containing beverages or food and grapefruit juice overnight before receiving the cocktail orally. They provided blood spots for the probes' concentrations at 2, 3, and 6 h after ingestion and were asked about adverse events. RESULTS A total of 265 healthy adult volunteers were included from Ethiopia, Oman, and the Czech Republic. The mean plasma concentrations at the 2-h sampling time of each probe drug in the total sample were: 1663 ng/mL for caffeine, 8 ng/mL for bupropion, 789 ng/mL for flurbiprofen, 6 ng/mL for dextromethorphan, 2 ng/mL for midazolam, 35 ng/mL for fexofenadine, and 103 ng/mL for omeprazole. Four adverse events were observed representing an occurrence of 1.5%. All these events were categorized as mild to moderate, non-serious, and resolved spontaneously. A causal link with the cocktail cannot be excluded because of the temporal relationship but is at most evaluated as possible according to the World Health Organization-Uppsala Monitoring Centre causal assessment system. CONCLUSIONS In this research, healthy volunteers from three different human populations were phenotyped with the Geneva cocktail. Four adverse events were observed, confirming the safety of this cocktail that is given at lower than clinically relevant doses and therefore results in concentrations lower than those reported to cause adverse events.
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Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study.
Vicente, J, Zusterzeel, R, Johannesen, L, Ochoa-Jimenez, R, Mason, JW, Sanabria, C, Kemp, S, Sager, PT, Patel, V, Matta, MK, et al
Clinical pharmacology and therapeutics. 2019;(4):943-953
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Abstract
Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J-Tpeak (J-Tpeak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10-subject-per-drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ-Tpeak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether-à-go-go related gene (hERG), prolonged ΔΔQTc and ΔΔJ-Tpeak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced ΔQTc prolongation, but shortened ΔJ-Tpeak c and prolonged ΔTpeak -Tend . Absence of J-Tpeak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration-response in some cases.
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Effects of a Fixed-Dose Co-Formulation of Daclatasvir, Asunaprevir, and Beclabuvir on the Pharmacokinetics of a Cocktail of Cytochrome P450 and Drug Transporter Substrates in Healthy Subjects.
Garimella, T, Tao, X, Sims, K, Chang, YT, Rana, J, Myers, E, Wind-Rotolo, M, Bhatnagar, R, Eley, T, LaCreta, F, et al
Drugs in R&D. 2018;(1):55-65
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BACKGROUND A fixed-dose combination of daclatasvir (DCV; hepatitis C virus NS5A inhibitor), asunaprevir (ASV; non-structural protein 3 inhibitor), and beclabuvir (BCV; non-structural protein 5B inhibitor) is approved in Japan for hepatitis C virus genotype 1. OBJECTIVE The objective of this study was to assess the combination's drug-drug interaction potential in vivo using a validated cocktail of eight cytochrome P450 (CYP) and transporter probes. METHODS We conducted an open-label single-sequence study in healthy adults (n = 20) given single-dose caffeine (CYP1A2 substrate), metoprolol (CYP2D6), flurbiprofen (CYP2C9), montelukast (CYP2C8), omeprazole (CYP2C19), midazolam (CYP3A4), digoxin (P-glycoprotein), and pravastatin (organic anion-transporting polypeptide), alone or with steady-state twice-daily DCV/ASV/BCV 30/200/75 mg (with or without additional BCV 75 mg to adjust for higher exposure in hepatitis C virus infection). RESULTS Daclatasvir/asunaprevir/beclabuvir did not affect CYP1A2, CYP2C8, or CYP2C9; the probe maximum observed concentration and area under the concentration-time curve extrapolated to infinite time geometric mean ratios and 90% confidence intervals were all within the 0.8-1.25 bioequivalence range. Beclabuvir showed moderate dose-dependent CYP2C19 induction; omeprazole maximum observed concentration and area under the concentration-time curve from 0 to the last quantifiable concentration were lower with additional BCV [geometric mean ratio 0.36 (90% confidence interval 0.23-0.55) and 0.34 (0.25-0.46), respectively] than without [0.57 (0.42-0.78), 0.48 (0.39-0.59)]. Weak-to-moderate CYP3A4 induction was observed, plus weak CYP2D6, P-glycoprotein, and organic anion-transporting polypeptide inhibition [maximum observed concentration and area under the concentration-time curve extrapolated to infinite time without additional BCV: midazolam 0.57 (0.50-0.65), 0.53 (0.47-0.60); metoprolol 1.40 (1.20-1.64), 1.71 (1.49-1.97); digoxin 1.23 (1.12-1.35), 1.23 (1.17-1.29); pravastatin 2.01 (1.63-2.47), 1.68 (1.43-1.97)]. CONCLUSIONS No dose adjustments with DCV/ASV/BCV are indicated for CYP1A2, CYP2C8, CYP2C9, or P-glycoprotein substrates. CYP3A4, CYP2D6, and OATP substrates should be co-administered with caution. Co-administration with agents solely metabolized by CYP2C19 is not recommended.
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Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers.
Lenuzza, N, Duval, X, Nicolas, G, Thévenot, E, Job, S, Videau, O, Narjoz, C, Loriot, MA, Beaune, P, Becquemont, L, et al
European journal of drug metabolism and pharmacokinetics. 2016;(2):125-38
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This phase I, pilot clinical study was designed to evaluate the safety and the pharmacokinetic (PK) profiles of the CIME (Metabolic Identity Card) combination of ten drugs, with a view to its use as a phenotyping cocktail. Ten healthy Caucasian subjects were orally dosed with the CIME combination (caffeine-CYP1A2, repaglinide-CYP2C8, tolbutamide-CYP2C9, omeprazole-CYP2C19, dextromethorphan-CYP2D6, midazolam-CYP3A, acetaminophen-UGT1A1, 6&9 and 2B15, digoxin-P-gp, rosuvastatin-OATP1B1&3 and memantine-active renal transport). Blood was collected over 3 days and on day 7. CIME probes and relevant metabolites were assayed by LC-MS/MS and PK parameters were calculated. Main results were: (1) good safety with reversible mild or moderate adverse effects, (2) an analytical method able to quantify simultaneously the 10 probes and the major metabolites, (3) calculation of PK parameters for all probes in general agreed with published values, and (4) identification of the low CYP2D6 metabolizer. This pilot study showed that the CIME combination was well tolerated and that its pharmacokinetics could be accurately measured in healthy volunteers. This combination can now confidently be checked for sensitivity and specificity and for lack of interaction to be validated as a phenotyping cocktail.
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[Evaluation of drug administration through enteral feeding tubes in hospitalized patients].
de Amuriza Chicharro, N, Romero Jiménez, RM, Valero Zanuy, MA, Gomis Muñoz, P, Herreros de Tejada, A
Nutricion hospitalaria. 2012;(3):879-88
Abstract
OBJECTIVE To describe the administration of drugs through nasogastric tubes by the nursing staff of a tertiary hospital and to identify the most common administration errors. METHODS An observational study was carried out between November of 2010 and March of 2011. The study population was the nursing staff of the hospital. A questionnaire was created asking about the daily practice of drugs administration through the nasogastric tube; a score was assigned to each question. A document on correct administration techniques of drugs through the nasogastric tube was elaborated, which served for the comparison of the answers obtained. RESULTS A total of 162 surveys were answered. Most of the staff (44.5%) had a deficient knowledge on the proper administration techniques. 69.7% of the staff stated to have grinded some time a tablet with enteric coverage, and 66.2% a tablet with modified release. A significant lower number of perceived obstructions per month was obtained in those nurses with higher degree of knowledge, in those consulting the Pharmacy Department when they had doubts, and in those never having grinded a tablet with enteric coverage of modified release. CONCLUSIONS It is observed that the knowledge on proper administration of drugs through the nasogastric tube by the nursing staff is deficient; therefore, it would be convenient to carry out specific training courses as well as a closer collaboration between the Pharmacy department and the Nursing units.
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Intranasal delivery of drugs to eustachian tube orifice.
Karagama, YG, Rashid, M, Lancaster, JL, Karkanevatos, A, William, RS
The Journal of laryngology and otology. 2011;(9):934-9
Abstract
BACKGROUND Intranasal medication administration which aims to deliver to the eustachian tube orifice has been adopted for the management of a number of otological conditions, acting via a reduction in tubal oedema and improved ventilation. Evidence for the optimal head position for such drug administration is limited. We compared four different positions and also assessed spray versus drop formulation, to determine optimal delivery conditions. METHODS Prospective, five-period, cross-over study using methylene blue dyed saline in a drops or spray container. Five healthy volunteers tested the Mygind, Ragan, Mecca and 'head back' head positions. Nasal spray drug delivery in the most effective head position was then compared with drops drug delivery (administered in the head back position). Intranasal delivery was assessed photographically using a 30° rigid naso-endoscope. RESULTS Maximal nasal drops delivery was achieved with the Mygind and Ragan positions. Drops were more successful than spray in reaching the eustachian tube orifice. CONCLUSION The Mygind and Ragan positions are best for eustachian tube orifice drug delivery, and drops preparations are better than spray preparations.
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In vitro dissolution/permeation system to predict the oral absorption of poorly water-soluble drugs: effect of food and dose strength on it.
Kataoka, M, Itsubata, S, Masaoka, Y, Sakuma, S, Yamashita, S
Biological & pharmaceutical bulletin. 2011;(3):401-7
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The aim of the present work was to confirm the usefulness of the dissolution/permeation system (D/P system) in the estimation of human oral absorption of poorly water-soluble drugs. The D/P system, which can simultaneously evaluate drug absorption processes, dissolution and permeation, can predict the oral absorption of poorly water-soluble drugs in fasted and fed humans, with a correlation between in vivo oral absorption (% of absorbed) and in vitro permeated amount (% of dose/2 h) in the D/P system. The oral absorption (fraction of absorbed dose, %) of poorly water-soluble drugs in the fasted and fed states was predicted using the D/P system. The effect of food on the oral absorption of various drugs estimated by the D/P system significantly correlated with clinical data (correlation coefficient: r(2)=0.924). Moreover, the proportion of oral absorption of cilostazol was predicted to decrease with an increase in its dose strength, which significantly correlated with in vivo human absorption. Consequently, the D/P system was demonstrated to be a useful in vitro system for prediction of the oral absorption of poorly water-soluble drugs.
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Concentration-dependent effects of polyethylene glycol 400 on gastrointestinal transit and drug absorption.
Schulze, JD, Waddington, WA, Eli, PJ, Parsons, GE, Coffin, MD, Basit, AW
Pharmaceutical research. 2003;(12):1984-8
Abstract
PURPOSE The aim of the study was to investigate the effect of different concentrations of polyethylene glycol 400 (PEG 400) on liquid transit through, and ranitidine absorption from, the gastrointestinal tract. METHODS Six healthy male volunteers received, on four separate occasions, 150 mL water containing 150 mg ranitidine and either 0 (control), 1,2.5, or 5 g PEG 400. The solutions were radiolabeled with technetium-99m to allow their gastrointestinal transit to be followed using a gamma camera. Urine samples were collected over a 24-h period to assess the amount of ranitidine excreted and hence absorbed. RESULTS No significant differences in gastric emptying were noted between the four solutions. In contrast, the presence of 1, 2.5, and 5 g PEG 400 reduced the mean small intestinal transit times of the solutions by 9, 20, and 23%, respectively, against the control. In terms of drug absorption, the mean cumulative amount of ranitidine excreted was reduced by 38% in the presence of both 2.5 and 5 g PEG 400, although it was significantly increased by 41% in the presence of 1 g PEG 400. CONCLUSIONS The results show that low concentrations of PEG 400 enhance the absorption of ranitidine possibly via modulation of intestinal permeability, while high concentrations have a detrimental effect on ranitidine absorption presumably via a reduction in the small intestinal transit time.
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Determination of in vivo absorption, metabolism, and transport of drugs by the human intestinal wall and liver with a novel perfusion technique.
von Richter, O, Greiner, B, Fromm, MF, Fraser, R, Omari, T, Barclay, ML, Dent, J, Somogyi, AA, Eichelbaum, M
Clinical pharmacology and therapeutics. 2001;(3):217-27
Abstract
BACKGROUND AND AIMS The contribution of the gastrointestinal tract in comparison with the liver for the low and variable bioavailability of orally administered drugs is still poorly understood. Here we report on a new intestinal perfusion technique for the direct assessment of absorption, metabolism, and transport of drugs by the intestinal wall. METHODS In 6 healthy volunteers a multilumen perfusion catheter was used to generate a 20-cm isolated jejunal segment that was perfused with 80 mg verapamil. Simultaneously, 5 mg [(2)H(7)]verapamil was given intravenously. Blood, perfusate, and bile samples were analyzed for parent verapamil and its major metabolites. RESULTS The mean fraction of the verapamil dose absorbed from the 20-cm segment was 0.76 but substantial interindividual variability (0.51-0.96) was shown. Bioavailability was low (19.3%). The intestinal wall contributed to the same extent as the liver to extensive first-pass metabolism (mean extraction ratio, 0.49 versus 0.48). Substantial transport of verapamil metabolites from the systemic circulation via the enterocytes into the intestinal lumen was observed. Compared with biliary excretion, intestinal secretion into a 20-cm jejunal segment contributed to drug elimination to a similar extent. CONCLUSION First-pass metabolism by the intestinal wall is extensive and contributes to the same extent as the liver to low bioavailability of some drugs such as verapamil. Moreover, intestinal secretion is as important as biliary excretion for the elimination of metabolites.
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Drug use in pregnancy among Italian women.
Donati, S, Baglio, G, Spinelli, A, Grandolfo, ME
European journal of clinical pharmacology. 2000;(4):323-8
Abstract
OBJECTIVE To describe the use of drugs among Italian women during pregnancy and to compare it with other reports in Italy from the last 10 years. METHODS A random sample of women who delivered in 1995-1996 were interviewed with regard to the care they received during pregnancy, delivery and the post-natal period. Information on antenatal care included maternal reports on the use of drugs during pregnancy. RESULTS Of the 9004 women interviewed, 75% took at least one drug during pregnancy. Users took a median number of two drugs. Iron (51%) and vitamins (25%) dominate prescriptions throughout pregnancy. Fifteen percent of women reported treatment for threatened abortion and 27% for risk of pre-term delivery. The data do not differ from the drug exposure profile during pregnancy reported in other Italian studies. Logistic regression analysis of drug use (excluding haematologicals and nutritionals) shows an increased risk of usage for older women, the better educated, for those who reported health problems and those who had compulsory bed rest and/or hospitalisation during pregnancy. CONCLUSION Seventy-five percent of the women reported use of at least one drug during pregnancy. Haematological and nutritional drugs are over prescribed. Although hormones have been clearly proven to be ineffective in preventing threatened abortion, the study shows an almost unchanged and out of date prescription pattern of progestational drugs. In order to avoid unnecessary exposure to potential risk, maternity care procedures should be reviewed and strictly related to an "evidence-based" approach.