Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600mut melanoma patients.

BACKGROUND: Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mut melanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE. METHODS: We analysed PCD/T in patients treated with D+T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results. RESULTS: We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0ng/mL; interquartile range (IQR) [4-945]) and of PCT (median: 8.6ng/mL; IQR [5-39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P=0.06). However, no difference was observed between mean PCD/T of progressing patients (n=21; 125±183ng/mL and 9.3±3.6ng/mL, respectively) and responders (complete, partial or stable response) (n=13; 159±225ng/mL, P=0.58 and 10.6±24.4ng/mL, P=0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n=16) was significantly higher for female subjects (n=18; 11.5±4.8ng/mL) than for male subjects (8.8ng/mL±2.9, P=0.01), but no difference was observed between sex and CPD (P=0.32). CONCLUSION: Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment.

Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance.

BACKGROUND: Vemurafenib improves survival in advanced BRAFV600(mut) melanoma patients, but tolerance is often poor and resistance frequently occurs, without predictive factor. Our aim was to investigate for the first time a relationship between plasma vemurafenib concentration (PVC) and efficacy or tolerance. METHODS: Plasma samples from unresectable metastatic BRAFV600(mut) melanoma patients treated with vemurafenib monotherapy were prospectively collected at each tumour response evaluation (RECIST 1.1) or when adverse event occurred (CTCAE 4.0). PVC was measured with liquid chromatography-tandem mass spectrometry. Herein, we report on PVC at steady state (≥14 days after vemurafenib introduction or dose modification). Samples collected after first melanoma progression were excluded from the response analysis. All samples were analysed in the tolerance analysis. We kept the closest collected sample from the onset of each adverse effect or the one with the highest PVC in the absence of this adverse effect. Comparisons of means (Student's t-tests and Wilcoxon rank sum tests) and of frequencies (χ(2) tests) were carried out. A logistic regression analysis identified predictors of progression. RESULTS: We included 105 plasma samples in 23 patients (10M/13F). Initial vemurafenib dose was 960 mg b.i.d., reduced by 25% (8 patients) or 50% (2 patients) for intolerance in 10 patients (44%). PVC displayed high inter-individual variability (13.0-109.8 µg/ml, median 54.0). Mean PVC was lower at time of first progression (38.8 ± 19.7 µg/ml) than mean PVC found when tumour was stable or in partial or complete response (56.4 ± 21.0 µg/ml, P = 0.013, 21 patients). Logistic regression revealed that having a low PVC (P = 0.01) or brain metastasis (P = 0.01) were both significantly and independently associated with tumour progression. High PVC was not statistically significantly associated with the occurrence of adverse effects. CONCLUSION: PVC at steady state is highly variable and low PVC was associated with tumour progression, suggesting a new path to melanoma resistance to vemurafenib.

Cytochrome P-450-mediated herb and food-drug interactions can be identified in cancer patients through patient self-reporting with a tablet application: results of a prospective observational study.

BACKGROUND: Consumption of herbs, food used as medicine and dietary supplements (HFDSs) is common in cancer patients. Herbs and food-drug interactions (HFDIs) can lead to serious adverse effects and can be prevented. We previously reviewed cytochrome P-450 (CYP)-mediated HFDI for 261 HFDSs and we classified the risk of CYP inhibition and induction on a level of evidence scale from 1 (high evidence, supported by several clinical studies) to 5 (low evidence, only limited preclinical data). PATIENTS AND METHODS: We conducted a prospective, non-interventional study (NCT04128865) to assess whether self-assessment of patients could detect HFDI classified as 'probable' (i.e. level 1, 2 or 3 of the scale) in a population of cancer patients. Patients were invited through a tablet application to report their consumption of herbs, regular CYP-interacting food consumption and dietary supplements, as well as some clinical data and cancer treatments. The patient's completion of the survey could be supervised by a health care professional or not. A prespecified threshold of 5% of HFDIs classified as 'probable' detected with the application was deemed relevant. RESULTS: Between 29 March 2018 and 22 June 2018, 143 patients completed the survey. Ninety-five patients (66%) reported at least one current systemic cancer treatment and were included in the analyses. Seventy-four patients reported an intake of at least one HFDS (77.9%), while 21 patients reported no HFDS (22.1%). Twenty-two HFDIs classified as 'probable' were found in 16 patients (16.8%) with the application, which was significantly superior to the prespecified threshold (P = 0.02). The interactions were reported with food (n = 19, 86%) more frequently than with herbs (n = 3, 14%) or with dietary supplements (no interaction reported). CONCLUSIONS: Self-assessment of HFDS interaction with cancer treatment with an application is feasible and should be considered in daily routine. Prospective interventional studies should be conducted to better assess the clinical benefits of this approach.

Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes.

BACKGROUND: Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. METHODS: We searched the international pharmacovigilance database VigiBase for men (n=6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone. RESULTS: Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n=168) and/or TdP (n=68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio=1.4-4.7; P<0.05) with aLQTS, TdP, or sudden death. The minimum and median times to sudden death were 0.25 and 92 days, respectively. The androgen receptor antagonist enzalutamide was associated with more deaths (5430/31 896 [17%]; P<0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25µM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9ms (chronic; P<0.001), and generated afterdepolarizations and/or triggered activity in drug-treated cells (11/20 acutely and 8/15 chronically). Enzalutamide acutely and chronically inhibited delayed rectifier potassium current, and chronically enhanced late sodium current. Dihydrotestosterone (30nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells. CONCLUSION: QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.

Amiodarone interacts with simvastatin but not with pravastatin disposition kinetics.

The aim of this study was to determine the influence of amiodarone on the pharmacokinetics of simvastatin and pravastatin in humans. This was a prospective, crossover, randomized, open-label study performed in 12 healthy volunteers comparing the pharmacokinetics of a single oral dose of simvastatin (40 mg) or pravastatin (40 mg) taken alone and after 3 days of amiodarone (400 mg/day). Amiodarone increased simvastatin acid AUC (area under the plasma concentration-time curve)0-24 h, peak plasma concentration (Cmax), and t1/2 by 73% (P=0.02), 100% (P=0.02), and 48% (P=0.06), respectively, whereas it did not significantly alter pravastatin pharmacokinetics. Point estimates and 90% confidence intervals for simvastatin acid, simvastatin lactone, and pravastatin AUC0-24 h were 154% (109-216%), 155% (109-227%), and 86% (63-118%), respectively. If amiodarone and a statin have to be simultaneously prescribed, pravastatin should be preferred to simvastatin in order to avoid a drug interaction.

Clinical pharmacology of anti-angiogenic drugs in oncology.

Abnormal vasculature proliferation is one of the so-called hallmarks of cancer. Angiogenesis inhibitor therapies are one of the major breakthroughs in cancer treatment in the last two decades. Two types of anti-angiogenics have been approved: monoclonal antibodies and derivatives, which are injected and target the extracellular part of a receptor, and protein kinase inhibitors, which are orally taken small molecules targeting the intra-cellular Adenosine Triphosphate -pocket of different kinases. They have become an important part of some tumors' treatment, both in monotherapy or in combination. In this review, we discuss the key pharmacological concepts and the major pitfalls of anti-angiogenic prescriptions. We also review the pharmacokinetic and pharmacodynamics profile of all approved anti-angiogenic protein kinase inhibitors and the potential role of surrogate markers and of therapeutic drug monitoring.

Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin.

Essentials Rivaroxaban and dabigatran are substrates of the P-glycoprotein (P-gp) encoded by the ABCB1 gene. We tested the effect of ABCB1 polymorphisms and of a P-gp inhibitor on both drugs' pharmacokinetics. The ABCB1 genotype was not a clinically relevant determinant of both drugs' pharmacokinetics. Administration of P-gp inhibitors with dabigatran or rivaroxaban should be exercised with caution. SUMMARY: Background The direct oral anticoagulants (DOACs) dabigatran and rivaroxaban are both substrates of the P-glycoprotein (P-gp) transporter, encoded by the ABCB1 gene. Rivaroxaban is metabolized by cytochrome P450 A4 (CYP3A4). Interindividual variability in DOAC exposure and frequent P-gp-associated drug-drug interactions have been described in patients. Objective To assess the influence of ABCB1 polymorphisms on the pharmacokinetics of dabigatran and rivaroxaban, associated or not with clarithromycin, a P-gp and CYP3A4 inhibitor. Methods Sixty healthy male volunteers, selected according to ABCB1 genotype (20 homozygous mutated, 20 heterozygous mutated, and 20 wild-type for haplotype 2677-3435), were included in this randomized, two-center, crossover study. All received sequentially a single dose of dabigatran etexilate (300 mg) and rivaroxaban (40 mg) associated or not with clarithromycin. Peak plasma concentration and area under the curve (AUC) were compared across the three ABCB1 genotypes. The effect of clarithromycin on dabigatran or rivaroxaban pharmacokinetics was assessed. Results Interindividual coefficients of variation for AUC were 77% for dabigatran and 51% for rivaroxaban. ABCB1 genotype did not significantly affect drug pharmacokinetics: AUC ratios between mutant-allele carriers and wild-type volunteers were 1.27 (95% confidence interval [CI] 0.84-1.92) and 1.20 (95% CI 0.96-1.51) for dabigatran and rivaroxaban, respectively. Clarithromycin coadministration led to a two-fold increase in both drugs' AUC, irrespective of ABCB1 genotype: ratios of geometric means were 2.0 (95% CI 1.15-3.60) and 1.94 (95% CI 1.42-2.63) for dabigatran and rivaroxaban, respectively. Conclusions ABCB1 genotype is not a significant determinant of interindividual variability in dabigatran and rivaroxaban pharmacokinetics. The levels of one drug did not predict the levels of the other. Coadministration of a P-gp/CYP3A4 inhibitor with dabigatran or rivaroxaban may warrant caution in patients at risk of overexposure.

3-Hydroxybenzo[a]pyrene in the urine of smokers and non-smokers.

The people studied were male volunteers without occupational and dietary exposure to PAH: 27 smokers (10 cigarettes or more) and 27 non-smokers matched for age and socio-professional category. For each person, all the 24h voided urine samples were reassembled in a single sample. 1-Hydroxypyrene (1-OHPy) and 3-hydroxybenzo[a]pyrene (3-OHBaP) were then determined by automated column-switching high-performance liquid chromatography. Urinary 1-OHPy ranged from 0.041 to 0.530 micromol/molCreatinine (arithmetic mean 0.144, median 0.115) for smokers and from 0.01 to 0.148 mmol/molCreatinine (arithmetic mean 0.044, median 0.032) for non-smokers. These values are close to those of some other studies. Urinary 3-OHBaP ranged from <0.01 to 0.084 nmol/molCreatinine (arithmetic mean 0.030, median 0.023) for smokers and from <0.01 to 0.045 nmol/molCreatinine (arithmetic mean 0.014, median 0.011) for non-smokers. Considering more particularly the urinary 3-OHBaP values, the influence of smoking could be important among workers exposed to low levels of BaP (<100 ng/m(3)) and the concentrations for smokers were equivalent to most of the preshift values of exposed workers. The dietary BaP intake was slightly lower than the BaP intake for an average smoker. From the present study, temporary basic reference levels may be proposed for urinary 3-OHBaP.

[Cardiac tolerance of moxifloxacin: Clinical experience from a large observational French study in usual medical practice (IMMEDIAT study)]. / Tolérance cardiaque de la moxifloxacine: expérience clinique issue d'une large étude observationnelle française en pratique médicale usuelle (étude IMMEDIAT).

BACKGROUND: Moxifloxacin (Izilox) is prescribed for bacterial respiratory tract infections. ECG analysis done in clinical trials showed a mean QT prolongation at 6 ms that could lead to Torsades de Pointe. However, Izilox was well tolerated during clinical trials. To confirm the correct safety profile of Izilox in a large sample of patients, a French PMS study - MMEDIAT - was carried out in usual medical practice. METHODS: This prospective observational uncontrolled and monitored study was conducted in 13,578 patients with respiratory tract infection and treated with moxifloxacin 400 mg daily (duration: 5 to 10 days in accordance to the Market Authorization). Any clinical event being potentially a surrogate of a ventricular rhythm disorder ("critical event") were collected and analyzed by a Scientific Committee in charge to determine the potential cardiac origin of the reported event and to establish a causal relationship with the treatment. RESULTS: Among 13,578 patients, 1046 adverse events (678 patients [5%]) were reported, including 854 drug related events (564 patients [4.15%]). Of these 1046 adverse events, 95 (62 patients [0.46%]) were serious. A total of 189 critical adverse events (159 patients [1.2%]) were reviewed by the Scientific Committee. After analysis, 34 adverse events (28 patients [0.21%]) were assessed from potential cardiac origin. Of these 34 adverse events, 25 (19 patients [0.14%]) were assessed as drug-related: palpitations [13 patients], tachycardia [4 patients], malaise [4 patients], vertigo [3 patients] and pallor [1 patient]. All adverse events were transient and had favourable outcome. CONCLUSION: This PMS study confirmed that Izilox is well-tolerated in usual medical practice, in adequation with the safety data obtained in clinical trials.

Sex differences in the prognosis of congestive heart failure: results from the Cardiac Insufficiency Bisoprolol Study (CIBIS II).

BACKGROUND: Whether female sex is associated with a better prognosis in patients with congestive heart failure (CHF) remains uncertain. The Cardiac Insufficiency Bisoprolol Study (CIBIS) II showed that bisoprolol reduced all-cause mortality and morbidity rates in CHF patients treated with diuretics and ACE inhibitors. We examined whether survival was different in men (n=2132) and women (n=515) enrolled in CIBIS II. METHODS AND RESULTS: Women differed from men with regard to age, NYHA functional classification, primary cause of CHF, and risk factors such as left bundle-branch block. After adjustment for baseline differences, the probability of all-cause mortality was significantly reduced by 36% in women compared with that in men (hazard ratio 0.64, 95% CI 0.47 to 0.86, P:=0.003). Women also had a 39% reduction in cardiovascular deaths (hazard ratio 0.64, 95% CI 0.45 to 0.91, P:=0.01) and a 70% reduction in deaths from pump failure (hazard ratio 0.30, 95% CI 0.13 to 0.70, P:=0.005) compared with men. Kaplan-Meier survival analysis revealed a significant reduction in all-cause mortality among women treated with bisoprolol compared with men (6% versus 12% P:=0.01) but not among women treated with placebo (13% versus 18%, P:=0.10). However, this sex/ss-blocker effect was not significant in multivariate analysis. CONCLUSIONS: These results indicate that regardless of ss-blocker treatment and baseline clinical profile, female sex is a significant independent predictor of survival in patients with CHF.

Rate dependence of ventricular extrasystoles: computer identification and quantitative analysis.

A new computer program was designed to identify and quantify the rate dependence of arrhythmias using 24 hour Holter tape recordings. The program was used in 10 untreated apparently healthy patients with fixed, coupled, isolated monomorphic ventricular extrasystoles. The second cycles of two consecutive sinus cycles were grouped according to whether or not they were followed by a ventricular extrasystole. Each of these sinus cycles was further analysed by cycle length during successive one hour periods. From the number of cycles in each cycle length class, identification and quantification of an upper or lower limit, or both, of cycle length beyond which ventricular extrasystoles disappeared were possible. Upper and lower limits were observed in 10 and eight of the 10 patients respectively. An upper and a lower limit were identifiable (mean(SD) 9.3(5.1) and 8.4(5.8) times per recording respectively). Values of both types of limits varied throughout tape recording. A positive significant correlation was found between the values of upper and lower limits and the mean sinus cycle length during the corresponding hour in nine of the 10 and eight of the eight patients respectively. The type of relation observed suggests that heart rate directly alters limits or that heart rate and limits are under the same influence of the autonomic nervous system. It is concluded (a) that identification and quantification of the rate dependence of arrhythmias is possible using this computer program; and (b) that, in patients with ventricular extrasystoles and apparently normal hearts, upper and lower limits vary and are related to heart rate.

CYP2D6- and CYP3A-dependent metabolism of dextromethorphan in humans.

The metabolism of dextromethorphan, a drug used to probe genetically determined CYP2D6 activity has been investigated in vivo and in vitro. In vitro, kinetic parameters were determined in adult microsomes: Km for the O-demethylation was much lower than for N-demethylation (7 versus 650 microM) but Vmax was comparable. Fetal liver microsomes actively catalysed the N-demethylation of dextromethorphan, with kinetic parameters (Vmax and Km) quite similar in fetal and adult microsomal preparations while the O-demethylation did not exceed 5% of adult activity. In microsomes, the N-demethylation was inhibited by antibodies raised against CYP3A subfamily members although fetal microsomes were much less sensitive to immunoinhibition than adult microsomes. In vivo, urinary excretion of dextromethorphan and its three demethylated metabolites was examined in 155 adult volunteers and compared between extensive (n = 144, 92.9%) and poor (n = 11, 7.1%) metabolizers. The O-demethylation to dextrorphan is the rate-limiting step of metabolism. In 2D6 poor metabolizers, the N-demethylation to 3-methoxymorphinan is slightly higher than in 2D6 extensive metabolizers but does not compensate defective O-demethylation. The frequency distribution histograms of dextromethorphan/dextrorphan and 3-methoxymorphinan/3-hydroxymorphinan metabolic ratios appeared bimodally distributed, reflecting the participation of CYP2D6 in the O-demethylation reaction. They clearly differed from the random distribution of dextromethorphan/3-methoxymorphinan, and dextrorphan/3-hydroxymorphinan ratios among the population. These data clearly suggest that the N-demethylation of dextromethorphan is dependent on CYP3A and that both CYP2D6 and CYP3A are involved in the overall metabolism of dextromethorphan.

Use of heterologously expressed human cytochrome P450 1A2 to predict tacrine-fluvoxamine drug interaction in man.

The aim of the present study was to evaluate the use of recombinant human cytochrome P-450 1A2 (rH-CYP1A2) in studies performed in vitro in order to predict metabolic drug-drug interactions occurring in man. In vitro metabolism of tacrine (a CYP1A2 probe) in the presence and absence of fluvoxamine, a CYP1A2 inhibitor, was investigated in human liver mircrosomes and with different rH-CYP. Vmax, Km and Ki determined with human liver microsomes were compared with those observed using rH-CYP1A2, assuming that 1 mg of liver microsomes contains, on average, 69 pmol of CYP1A2. The extent of tacrine metabolism inhibition procured by fluvoxamine with rH-CYP1A2, was compared with previous results observed in man. The Vax and Km for 1-hydroxytacrine formation rates obtained with rH-CYP1A2 were in good agreement with those observed in human liver microsomes (175+/-9 versus 140+/-60 pmol/min/mg for Vmax and 14+/-2 versus 16+/-2 microM for Km, respectively. The Ki of fluvoxamine on 1-hydroxytacrine formation rate observed with rH-CYP1A2 was similar to that observed with human liver microsome (0.35+/-0.05 versus 0.20+/-0.20 microM, respectively). Using the Km, Vmax and Ki determined with rH-CYP1A2, we calculated that fluvoxamine produced an inhibition of 1-, 2- and 4-hydroxytacrine formation rate of 91, 87 and 88%, respectively, in the range of tacrine and fluvoxamine concentrations observed in man. These percentages of inhibition calculated in vitro were in agreement with the percentage of fluvoxamine-dependent decrease in tacrine apparent oral clearance previously observed in man (83+/-13%). We conclude that human CYP1A2 expressed in yeast is a powerful tool to predict and to quantify drug-drug interactions in man.

Effect of a single oral dose of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects.

BACKGROUND: Moxifloxacin is a new fluoroquinolone. In vitro studies have suggested that it could prolong ventricular repolarization. The main objective of this study was to measure the actual effect of single oral doses of moxifloxacin on QT interval duration in healthy volunteers. METHODS: Nine men and 9 women participated in a double-blind, randomized, placebo-controlled, crossover study. Each participant received single oral doses (400 mg and 800 mg) of moxifloxacin or placebo. At the time of expected moxifloxacin maximum concentration, several electrocardiographic recordings were obtained at rest and during the course of a submaximal exercise test. QT interval and the corresponding RR interval value were measured within a wide range of RR intervals in each subject. RESULTS: ANOVA showed that both moxifloxacin doses increased mean QT intervals compared with placebo. The mean QT interval duration at RR = 1000 ms was 379 +/- 24 ms during placebo, 394 +/- 33 ms during moxifloxacin 400 mg (P < .05), and 396 +/- 28 ms during moxifloxacin 800 mg (P < .05). Moxifloxacin-induced QT interval prolongation remained significant at all tested heart rates. The increase in QT interval duration relative to placebo remained between 2.3% +/- 2.8% and 4.5% + 3.8% across the range of RR intervals tested. CONCLUSION: Moxifloxacin prolongs QT interval duration. The amplitude of this effect is small, and the risk of moxifloxacin-induced torsades de pointes is expected to be minimal when the drug is administered at the recommended dose of 400 mg/d. However, moxifloxacin should not be used in patients with predisposing factors of torsades de pointes such as electrolyte disturbances and bradycardia or during coadministration of proarrhythmic drugs.

Comparison of tolerance to intravenous nitroglycerin during nicorandil and intermittent nitroglycerin patch in healthy volunteers.

BACKGROUND: Nitrate tolerance is associated with a loss in the hemodynamic response to nitrate during repeated administration. Nicorandil is a new potassium channel agonist with additional nitrate properties. The aim of this study was to determine whether 7-day nicorandil (10 mg orally twice a day) administration attenuates the response to single-dose intravenous nitroglycerin (0.45 mg over 1 minute) in comparison with 7-day intermittent nitroglycerin patch administration (10 mg for 16 of 24 hours). METHODS: This was an open, randomized crossover study performed in 12 healthy volunteers. Blood pressure, heart rate, and their oscillations were measured with use of a noninvasive device. Low-frequency oscillations (66 to 129 mHz) of blood pressure reflect sympathetic activity. Reflex sympathetic activation was measured as after versus before intravenous nitroglycerin difference in low frequency oscillations of blood pressure and heart rate on day 0 and day 7 of each treatment period. Measurements after single-dose intravenous nitroglycerin included the maximum decrease in systolic blood pressure and maximum increase in heart rate and sympathetic activation. Tolerance in each group was assessed as the difference in each parameter between day 7 and day 0. RESULTS: Attenuation of the intravenous nitroglycerin-induced decrease in systolic blood pressure (day 7 - day 0) was - 10 +/- 10 mm Hg during use of the nitroglycerin patch and -2 +/- 11 mm Hg during nicorandil (p = 0.03). Similarly, the change in low frequency oscillations of systolic blood pressure was -79 +/- 144 mm Hg-Hz-1/2 during nitroglycerin administration and 60 +/- 139 mm Hg-Hz-1/2 during nicorandil administration (p = 0.04). CONCLUSION: These results indicate that 7-day administration of nicorandil does not attenuate single-dose intravenous nitroglycerin-induced hemodynamic changes or sympathetic activation. In healthy volunteers and at this dosage (10 mg twice a day), cross tolerance between nicorandil and nitroglycerin does not occur.

Pharmacokinetic and pharmacodynamic modeling of the effects of oral and intravenous administrations of dofetilide on ventricular repolarization.

OBJECTIVES: To examine the pharmacokinetics and the relation between plasma concentrations of the new potassium channel blocker dofetilide and QTc prolongation on the surface electrocardiogram after oral and intravenous administration. METHODS: Ten healthy volunteers received a single dose of 0.5 mg dofetilide orally and intravenously (over 30 minutes) in a randomized crossover study. The QTc interval versus dofetilide plasma concentration was analyzed by use of pharmacokinetic and pharmacodynamic modeling techniques. RESULTS: Dofetilide absolute bioavailability and systemic clearance were 92% +/- 9% and 0.35 +/- 0.05 L/hr/kg, respectively. Mean maximum increase in QTc interval duration was 99 msec (27%) and 61 msec (16%) after intravenous and oral administration, respectively. A counterclockwise hysteresis loop between dofetilide plasma concentrations and QTc interval duration was observed after intravenous infusions in all subjects, whereas direct linear relationships were observed after oral administrations in eight of 10 subjects. Pharmacokinetic-pharmacodynamic modeling showed the consistency of the effect versus concentration relationships obtained with the two routes of administration. With use of a maximum effect (Emax) model and data obtained after intravenous infusion, mean maximum QTc prolongation (Emax) was 121 +/- 57 msec and mean dofetilide plasma concentration associated with half the maximum effect (EC50) was 2.2 +/- 0.6 ng/ml. Pharmacokinetic-pharmacodynamic modeling was useful in detecting the maximum effect and in describing the plasma concentration versus effect relationship during intravenous infusion of dofetilide but was otherwise not superior to analyses performed with postdistribution data. CONCLUSION: We conclude that dofetilide prolongs QTc interval duration in a concentration-dependent manner in normal volunteers during sinus rhythm and that pharmacokinetic-pharmacodynamic modeling is useful for examination of maximum QTc prolongation induced by dofetilide.

Prospective pharmacokinetically based development of effective infusion regimens for ACC-9358, a new antiarrhythmic drug.

In this study we evaluated the clinical pharmacology of intravenous ACC-9358, a new antiarrhythmic drug derived from a Chinese herbal remedy. In a first-study phase, 0.125 to 1.0 mg/kg during 10 minutes was administered to six patients with chronic nonsustained ventricular arrhythmias. These data were then used to design 3-hour infusions to maintain stable plasma concentrations: these infusions suppressed arrhythmias by 90% or greater for 2 1/2 hours or more at plasma concentrations of 114 to 1010 ng/ml (mean, 400 +/- 421 ng/ml [SD]), and with QRS interval increases of 2.5% to 8.8% (5.1% +/- 2.9%). Mean clearance was 478 +/- 151 ml/min, and elimination half-life was 19.1 +/- 6.1 hours. ACC-9358 did not produce adverse effects in this study. ACC-9358 shows antiarrhythmic activity in humans at concentrations that prolong QRS only slightly and do not alter rate-corrected QT; further studies in other patient populations, at dosages and plasma concentrations defined here, are required to establish a clinical role for ACC-9358. The pharmacokinetically based dose-ranging approach allowed the safe initial evaluation of ACC-9358 in patients.

Influence of amiodarone on genetically determined drug metabolism in humans.

Amiodarone has been shown to interact with the nongenetically determined hepatic elimination of several drugs, including phenytoin and digoxin. Its influence on genetically determined metabolic pathways has not been studied in humans. We examined the effects of oral amiodarone therapy on the genetically determined metabolism of isoniazid (N-acetyltransferase), mephenytoin (cytochrome P450MEPH), and dextromethorphan (CYP2D6). Eight patients with arrhythmias were studied before and 76 +/- 16 days after amiodarone (loading dose of 1000 mg/day for 10 days followed by a maintenance dose of 200 to 400 mg/day). Genetically determined enzyme activity was assessed indirectly by calculating the metabolic ratio (parent drug/metabolite in 8-hour urine for CYP2D6 and P450MEPH and N-acetylisoniazid/isoniazid in plasma for N-acetyltransferase) after oral administration of the parent compounds. At the time of phenotyping, plasma concentrations of amiodarone and N-desethylamiodarone were 0.66 +/- 0.35 micrograms/ml and 0.65 +/- 0.26 micrograms/ml, respectively. Amiodarone increased the log(metabolic ratio) of dextromethorphan from a median of -2.5 (range, -2.9 to -2.0) to a median of -1.9 (range, -2.5 to -1.5; p less than 0.02) but did not alter the metabolic ratio of mephenytoin or isoniazid. The amount of dextromethorphan excreted in urine increased from a median of 0.084 mumol/8 hours (range, 0.041 to 0.161 mumol/8 hours) to a median of 0.205 mumol/8 hours (range, 0.064 to 0.288 mumol/8 hours; p less than 0.02) and the amount of its metabolite (dextrorphan) tended to decrease from a median of 26 mumol/8 hours (range, 15 to 37 mumol/8 hours) to a median of 20 mumol/8 hours (range, 7 to 27 mumol/8 hours; p less than 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)