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Therapeutic drug monitoring (TDM) involves measuring and interpreting drug concentrations in biological fluids to adjust drug dosages. In onco-hematology, TDM guidelines for oral molecular targeted therapies (oMTTs) are varied. This study evaluates a quantitative approach with a score to predict the clinical usefulness of TDM for oMTTs. We identified key parameters for an oMTT's suitability for TDM from standard TDM recommendations. We gathered oMTT pharmacological data, which covered exposure variability (considering pharmacokinetic (PK) impact of food and proton pump inhibitors), technical intricacy (PK linearity and active metabolites), efficacy (exposure-response relationship), and safety (maximum tolerated dose, and exposure-safety relationship). To assess the validity and the relevance of the score and define relevant thresholds, we evaluated molecules with prospective validation or strong recommendations for TDM, both in oncology and in other fields. By September 1, 2021, the US Food and Drug Administration (FDA) approved 67 oMTTs for onco-hematological indications. Scores ranged from 15 (acalabrutinib) to 80 (sunitinib) with an average of 48.3 and a standard deviation of 15.6. Top scorers included sunitinib, sorafenib, cabozantinib, nilotinib, and abemaciclib. Based on scores, drugs were categorized into low (< 40), intermediate (≥ 40 and < 60), and high (≥ 60) relevance for TDM. Notably, negative controls generally scored around or under 40, whereas positive controls had a high score across different indications. In this work, we propose a quantitative and reproducible score to compare the potential usefulness of TDM for oMTTs. Future guidelines should prioritize the TDM for molecules with the highest score., (© 2024 The Authors. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Aims: Angiotensin-converting enzyme inhibitors (ACE-Is) and beta-blockers are associated with improved outcome in patients with chronic heart failure (CHF). In this post hoc analysis of the CIBIS III trial, we examined the influence of the order of drug administration on clinical events and achieved dose. We also assessed the relations between dose levels and baseline variables or adverse events., Methods and Results: In the CIBIS III trial, 1010 patients (mean age: 72.4 years; mean ejection fraction: 28.8%; male: 68.2%) with stable CHF were randomized to up-titration of monotherapy with either bisoprolol (target dose 10 mg o.d.) or enalapril (target dose 10 mg b.i.d.) for 6 months, followed by their combination for 6-24 months. Endpoints were mortality or all-cause hospitalization, mortality alone and mortality or cardiovascular hospitalization. The study drug (ACE-I or beta-blocker) was last prescribed at ≥50% of target dose to significantly more patients for the first initiated drug in both treatment groups (both P< 0.001). Sixty per cent of endpoints were reached during the monotherapy phase and randomized treatment during monotherapy was not a predictor of the three assessed outcomes. Monotherapy phase was the strongest independent predictor of outcome (P< 0.0001 for all endpoints). Older age, NYHA class III, impaired renal function, lower body weight and blood pressure at baseline, and hypotension, bradycardia and heart failure during treatment were associated with the inability to reach high dose of both study drugs., Conclusion: The order of drug administration plays an important role in whether CHF patients reach target doses of bisoprolol and enalapril. For both study drugs, the dose level reached was associated with baseline characteristics and adverse events. In CHF patients not treated with an ACE-I or a beta-blocker, the duration of monotherapy with either type of drug should be shorter than 6 months.

Background: Although oxytocin, a uterotonic agent, may cause short-term vasodilation that results in severe hypotension, it is still routinely given as an intravenous bolus injection during surgical suction curettage. Two reported cases of ventricular tachycardia after oxytocin bolus in patients with long QT interval syndrome led us to assess the effect of oxytocin on QT interval., Method: Thirty-eight healthy women scheduled for a surgical suction curettage with general anesthesia were enrolled. General anesthesia was induced by propofol and maintained by either propofol (n = 18) or sevoflurane (n = 20). Electrocardiographic recordings were obtained before and at 1, 2, 3, and 5 minutes after a 10-U intravenous bolus of oxytocin., Results: Intravenous oxytocin induced a pronounced QTc interval prolongation of 41 +/- 21 ms ( P < .0001), which was maximal 1 minute after administration. The QTc interval returned to control values 3 minutes after oxytocin bolus. Oxytocin bolus also induced an increase in heart rate of 19 +/- 10 beats/min and a significant decrease in systolic arterial pressure of 11 +/- 9 mm Hg (both P < .0001). The drug used to maintain anesthesia was not an independent factor of QT interval prolongation in ANOVA analysis., Conclusions: Oxytocin intravenous bolus induced a large and transient QTc interval prolongation, suggesting that it may lead to proarrhythmia in circumstances favoring QTc interval increase.

Objective: The aim of this study was to investigate the respective contribution of the different cytochrome P450 (CYP) 2C9 genetic polymorphisms to the interindividual variability of acenocoumarol pharmacodynamic response., Methods: A total of 263 healthy volunteers were genotyped for CYP2C9*2, CYP2C9*3, CYP2C9*4, and CYP2C9*5 alleles, as well as for the nicotinamide adenine dinucleotide phosphate, reduced, quinone oxidoreductase 1 genetic polymorphism (NQO1*2). Moreover, the 5'-flanking region of the CYP2C9 gene was investigated for new polymorphisms, and haplotype analysis was then performed. Finally, CYP2C9 phenotype was evaluated after a single oral dose of 4 mg of acenocoumarol. Factor VII coagulant activity was measured before and 24 hours after acenocoumarol intake., Results: The CYP2C9*3 allele was the only nonsynonymous single nucleotide polymorphism (SNP) influencing acenocoumarol pharmacodynamics; the percentages of remaining factor VII were 60% +/- 19%, 39% +/- 17%, and 17% for CYP2C9*1/CYP2C9*1, CYP2C9*1/CYP2C9*3, and CYP2C9*3/CYP2C9*3 subjects, respectively (P =.001). Among the white subjects, the CYP2C9 promoter showed the existence of 6 SNPs at positions G-1538A, T-1189C, G-1097A, G-982A, T-640 del, and G-620T with allelic frequencies of 0.085, 0.0398, 0.136, 0.086, 0.005, and 0.0138, respectively. Four major haplotypes could be inferred among white subjects. The haplotype that contains the CYP2C9*3 allele was the only one influencing acenocoumarol pharmacodynamics, explaining 14.3% of its interindividual variability. Body weight explained 5% of acenocoumarol pharmacodynamic variability, whereas the NQO1*2 allele had no significant effect., Conclusion: Overall, CYP2C9-related genetic variability accounts for 14% of the interindividual variability in acenocoumarol pharmacodynamic response. The information found by haplotype analysis is mainly related to the CYP2C9*3 SNP.

Background: Telithromycin is the first member of a new class of antimicrobials-the ketolides. The main objective of this study was to assess the effect of various oral doses of telithromycin on QT interval during single and repeated administrations., Methods: Seventeen men and 17 women participated in double-blind, placebo-controlled, crossover studies. Of these subjects, 18 (9 men and 9 women) received single and repeated oral doses of telithromycin (800 mg daily), clarithromycin (500 mg twice daily), or placebo (protocol 1). The other 16 subjects received a single oral dose (800 mg, 1600 mg, and 2400 mg) of telithromycin or placebo (protocol 2). At the time of expected telithromycin maximum concentration, several electrocardiographic recordings were obtained at rest and during the course of a submaximal exercise test. QT intervals were measured within a wide range of R-R intervals in each subject., Results: ANOVA showed that telithromycin did not increase QT interval at any dose compared with placebo. The greatest effect observed during any study period was a mean (+/-SD) change in QT-interval duration of 4.2 +/- 15.2 ms (ie, +1.2% +/- 4.0%, P not significant) at R-R = 1000 ms after repeated doses of 800 mg telithromycin. Outlier values (change in Bazett QTc from baseline >60 ms) from resting 12-lead electrocardiograms did not differ across treatment groups, including placebo., Conclusions: Telithromycin administered as repeated doses of 800 mg (recommended doses) or as single doses of up to 3 times this recommended dose did not increase the QT interval at any heart rate at rest and during effort. Telithromycin did not prolong QT-interval duration when administered to healthy young male and female subjects.

Background: On the basis of in vitro studies indicating that dipyridamole is an inhibitor for the MDR1 efflux membrane transporter P-glycoprotein, we postulated that dipyridamole could increase the bioavailability of digoxin, a P-glycoprotein substrate., Objectives: The main objective was to determine whether dipyridamole alters the bioavailability of digoxin. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by MDR1 genetic polymorphism in exon 26 (C3435T)., Material and Methods: (1) The effect of dipyridamole on in vitro P-glycoprotein-mediated, polarized transport of tritium-labeled digoxin was investigated in Caco-2 cell monolayers. (2) Twelve healthy volunteers participated in this open, randomized, 2-period crossover study, in which the effects of dipyridamole (300 mg/d for 3 days) versus placebo on the pharmacokinetics of a single oral dose of digoxin (0.5 mg) were compared. MDR1 genotyping (exon 26, C3435T) was determined before the study to include 6 homozygous CC and 6 homozygous TT subjects., Results: Dipyridamole inhibited [(3)H]digoxin transport in Caco-2 cells with a 50% inhibitory concentration value of 1.5 +/- 1.5 micromol/L. We observed a 20% and 13% increase in digoxin area under the plasma concentration-time curve (AUC) from 0 to 4 hours and AUC from 0 to 24 hours (P <.05), respectively, during dipyridamole administration, which was consecutive to an increase in digoxin absorption. Digoxin AUC from 0 to 4 hours and AUC from 0 to 24 hours were significantly higher among subjects harboring the TT compared with the CC MDR1 genotype: 7.5 +/- 1.2 ng x h x mL(-1) versus 6.1 +/- 0.8 ng x h x mL(-1) and 20.2 +/- 2.1 ng x h x mL(-1) versus 16.8 +/- 1.7 ng x h x mL(-1), respectively (P <.05). Digoxin pharmacokinetic modifications during the dipyridamole period were similar in both genotypes., Conclusion: Dipyridamole is an in vitro and in vivo P-glycoprotein inhibitor that increases intestinal digoxin absorption and digoxin plasma concentrations. In light of the modest changes in digoxin pharmacokinetics in the presence of dipyridamole, this drug interaction is probably clinically irrelevant.

Background: Halofantrine, an antimalarial drug that prolongs the QT interval, is metabolized into N-debutyl-halofantrine by cytochrome P450 (CYP) 3A4. Grapefruit juice increases the bioavailability of several orally administered CYP3A4 substrates by inhibiting CYP3A4 at the enterocyte level and could therefore increase the risk of halofantrine-induced QT interval prolongation. We studied the effect of grapefruit juice on halofantrine bioavailability and on QT interval prolongation associated with its oral administration., Methods: Twelve healthy male and female volunteers received 500 mg of halofantrine with 250 mL of water, orange juice, or grapefruit juice (250 mL once a day of regular strength for 3 days and once at 12 hours before halofantrine administration), in a random order, during a crossover study. Plasma pharmacokinetics of halofantrine and N-debutyl-halofantrine and QTc interval duration were studied during the following 168 hours., Results: Compared with water, grapefruit juice increased halofantrine area under the plasma concentration versus time curve (AUC) and peak plasma concentration by 2.8-fold +/- 1.5-fold (P <.0001) and 3.2-fold +/- 1.3-fold (P <.0001), respectively. There was a concomitant 2.4-fold +/- 1.6-fold decrease in N-debutyl-halofantrine AUC (P <.01) but no significant change in halofantrine elimination half-life. Maximum QTc interval prolongation increased from 17 +/- 6 ms when halofantrine was administered with water to 31 +/- 12 ms when it was administered with grapefruit juice (P <.0005). Multiple regression analysis showed that QTc interval prolongation was better correlated with halofantrine (partial r = 0.432; P <.0001) than with N-debutyl-halofantrine (partial r = 0.117; P <.01) concentrations. There was no significant difference between the water and orange juice study periods., Conclusions: Grapefruit juice increases halofantrine bioavailability and halofantrine-induced QT interval prolongation. Grapefruit juice should be contraindicated during administration of halofantrine.

Objectives: Our objectives were study the single- and repeated-dose pharmacokinetics and electrocardiographic effects (QRS duration) of a new controlled-release form of flecainide acetate compared with the immediate-release form and to examine the influence of CYP2D6 activity., Methods: Twenty-four healthy subjects (6 men and 6 women at both dosages) received single and repeated doses of 100 or 200 mg immediate-release and controlled-release flecainide in a randomized crossover design. Electrocardiograms were recorded and flecainide plasma concentrations were measured before administration and up to 96 hours after administration., Results: The controlled-release formulation had sustained-release properties, with a significantly lower maximum concentration (C(max)) and delayed time to reach C(max). Compared with the immediate-release formulation, the relative bioavailability of the controlled-release formulation at steady state was 0.85 +/- 0.17 and 0.89 +/- 0.17 for the 100-mg/day and 200-mg/day doses, respectively. Trough flecainide plasma concentration at steady state was bioequivalent for both formulations. Maximum and minimum QRS increases were not significantly different for either the immediate-release or the controlled-release form of flecainide after administration of both single and repeated doses. Mean QRS duration during a dosing interval at steady state correlated with mean plasma concentration for both forms (pooled data; P <.001). The 95% confidence interval for this regression was 26% narrower for the controlled-release form than for the immediate-release form. Flecainide-induced QRS prolongation and pharmacokinetics were not significantly influenced by CYP2D6 activity., Conclusions: Flecainide-induced QRS prolongation did not differ between the new controlled-release form and the immediate-release form. Flecainide plasma concentrations associated with the new controlled-release form predicted QRS prolongation with less variability compared with the immediate-release form. The CYP2D6 polymorphism did not appear to influence flecainide disposition kinetics or electrocardiographic effects at steady state.

Objective: To examine the mechanism of action of dual inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase, also called vasopeptidase inhibitors, we compared the effects of S21402 [(2S)-2-[(2S,3R)-2-thiomethyl-3-phenylbutanamido]propionic acid], which belongs to this pharmacologic class, with those of captopril, an ACE inhibitor, on blood pressure, endocrine parameters, and renal in healthy subjects with hypovolemia., Methods: Ten subjects participated to this double-blind, 2-period, randomized, crossover study. Hypovolemia was induced in these subjects with a 7-day treatment of hydrochlorothiazide. They received a single oral dose of 50 mg captopril or 250 mg S21402 on the last day of diuretic treatment. Blood pressure was measured, and urine and blood samples were collected before and during a 12-hour period after drug administration., Results: The plasma angiotensin II/angiotensin I ratio and aldosterone concentration decreased to the same degree with both drugs, 3 hours after dosing. Compared with captopril, S21402 increased levels of plasma atrial natriuretic peptide (P <.05) and urinary cyclic guanosine monophosphate (P <.001); these increases were the result of inhibition of neutral endopeptidase activity (P <.001). The increase in plasma renin concentration related to ACE inhibition was less marked (P <.001) after S21402 than after captopril. S21402, but not captopril, increased urinary sodium excretion (P <.05), without modifying blood pressure and creatinine clearance, whereas blood pressure transiently fell after captopril administration (P <.05)., Conclusions: In healthy hypovolemic subjects, the vasopeptidase inhibitor S21402 exhibits a natriuretic effect and does not affect blood pressure or glomerular filtration rate. In these conditions, the acute endocrine, vascular, and renal effects of vasopeptidase inhibition differ from those of ACE inhibition.

Background: Interferon alpha (IFN-alpha) is thought to be responsible for cytochrome P450 (CYP)-dependent drug interactions mediated by a decrease in CYP activities., Objectives: The objectives are to determine whether IFN-alpha and ribavirin can alter pretreatment CYP1A2, CYP2D6, CYP3A4 and N-acetyltransferase-2 activities after 1 month of treatment., Methods: Enzymatic activities were determined among 14 patients with chronic active hepatitis C before IFN-alpha (3. 10(6) U, 3 times a week) and ribavirin introduction and after 1 month of treatment. During both study periods, subjects received 80 mg dextromethorphan and 140 mg caffeine (1,3,7-trimethylxanthine [137X]). CYP3A4, CYP2D6, and NAT2 activities were assessed by use of urinary metabolic ratios of 3-methoxymorphinan/dextromethorphan, dextrorphan/dextromethorphan, and 5-acetylamino-6-formylamino-3-methyluracil (AFMU)/1-methylxanthine(1X). The plasma paraxanthine/caffeine ratio was used to measure CYP1A2 activity., Results: CYP3A4 and CYP2D6 activities tended to increase after 1 month of antiviral therapy, but the change did not reach statistical significance. CYP1A2 and NAT2 activities were not significantly modified after 1 month of antiviral treatment. Pretreatment activities were significantly lower than those previously observed in healthy volunteers for CYP2D6 (mean +/- SD, 148 +/- 139 versus 759 +/- 692; P =.0008) and CYP3A4 (0.18 +/- 0.06 versus 0.52 +/- 0.72; P =.0006). This difference was no longer statistically significant after 1 month of treatment, because CYP2D6 and CYP3A4 activities improved in 7 patients., Conclusion: In patients with chronic hepatitis C, pretreatment CYP3A4 and CYP2D6 activities were significantly lower than those observed in healthy volunteers. These differences disappeared after 1 month of antiviral treatment because of the restoration of these CYP activities in about half of the patients.

Objectives: Grapefruit juice is responsible for drug interactions mediated by intestinal cytochrome P4503A4 inhibition and possibly P-glycoprotein inhibition in enterocytes. Our main objective was to determine whether grapefruit juice alters the bioavailability of digoxin, a P-glycoprotein substrate. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by P-glycoprotein genetic polymorphism., Methods: Twelve healthy volunteers participated in this open randomized crossover study comparing the effect of grapefruit juice consumption (versus water) on the pharmacokinetics of a single oral dose of digoxin (0.5 mg). The P-glycoprotein genotype was determined according to MDR1 genetic polymorphism in exon 26 (C3435T)., Results: Grapefruit juice had no significant effect on the maximum plasma drug concentration (C(max)) of digoxin or the area under the plasma concentration-time curve (AUC) from time zero to 48 hours. However, there was a 9% increase in the digoxin AUC from time zero to 4 hours and from time zero to 24 hours (P =.01) during grapefruit juice administration. The digoxin renal clearance remained unchanged during both periods. No relationship between MDR1 C3435T genotype and early digoxin pharmacokinetic changes could be detected., Conclusion: The modest changes in digoxin pharmacokinetics observed during grapefruit juice ingestion do not support an important P-glycoprotein inhibition. Under our experimental conditions, grapefruit juice-mediated P-glycoprotein inhibition does not appear to play a relevant role in drug interactions, at least when assessed by use of digoxin disposition kinetics.

Objective: Our objective was to compare the sympathetic modulation induced by oral administration of a single dose of 20 mg of standard nifedipine, of 10 mg of amlodipine, and of 100 mg of mibefradil., Methods: Sixteen healthy male volunteers participated in this double-blind, randomized, placebo-controlled, crossover four-period study. The sympathetic modulation induced by treatments was evaluated during 24 hours after drug administration by neurohormonal dosages, hemodynamic parameter measurements, and spectral analysis of heart rate and blood pressure., Results: We observed a significant (P <.05) decrease in diastolic blood pressure 1 hour after the administration of nifedipine (62 +/- 9 to 59 +/- 5 mm Hg) with concomitant increases in heart rate (59 +/- 5 to 74 +/- 8 bpm) and neurohormones (53 +/- 18 to 83 +/- 50 pg/mL for aldosterone, 157 +/- 56 to 282 +/- 119 pg/mL for norepinephrine, and 9.8 +/- 5.5 to 40.2 +/- 97.1 pg/mL for active renin). No significant modification of these parameters was observed with amlodipine and mibefradil, except an isolated increase of norepinephrine plasma level 2 hours after the administration of mibefradil (133.1 +/- 67.1 to 210.9 +/- 92.5 pg/mL). The spectral analysis over 24 hours of Mayer waves of systolic blood pressure did not show any significant change over time in the different groups. When the analysis was performed during the first 4 hours after treatment administration, we observed a decrease of Mayer waves of systolic blood pressure with nifedipine (2.21 +/- 1.45 mm Hg(2) versus 3.53 +/- 1.85 mm Hg(2) with placebo). These results indicate that oral single doses of mibefradil and amlodipine do not induce baroreflex-mediated clinical changes in healthy volunteers. The single oral dose of nifedipine resulted in a marked increase in sympathetic tone and a decrease in systolic blood pressure variability early after oral administration., Conclusion: Mibefradil, the nondihydropyridine calcium antagonist, exerts much less sympathetic stimulation than nifedipine.

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.

Background: Glutathione conjugation of tacrine reactive metabolites depends in part on the activity of glutathione-S-transferases (GST), of which two isozymes (GST M1 and GST T1) are polymorphically expressed., Objective and Methods: To determine whether GST M1, GST T1, and the combined GST M1 and GST T1 null genotypes predict individual susceptibility to tacrine hepatotoxicity, 141 patients with mild to moderate Alzheimer's disease treated with tacrine were genotyped., Results: During the treatment period, 52 patients had elevated alanine aminotransferase (ALT) levels at least three times the upper limit of normal, whereas 89 patients had normal ALT values (< or = upper limit of normal). Both groups were comparable in demographic and clinical characteristics. Twenty-eight patients were found to be GST T1-negative (20%; with a 95% confidence interval [95% CI] from 13% to 27%), and 68 patients (48%; 95% CI from 40% to 57%) were GST M1-negative. The combined GST M1-T1 null genotype was observed in 18 patients (13%; 95% CI from 7% to 18%) of whom 13 had an elevated plasma ALT at least three times the upper limit of normal during the study period. Although the cumulative percentage of elevated plasma ALT tended to be higher in the GST M1 null genotype, neither GST M1 nor GST T1 alone could predict individual susceptibility to tacrine hepatotoxicity. Multivariate Cox hazards model showed that the association of the GST M1-T1 null genotype was an independent risk factor of hepatotoxicity., Conclusions: The presence of combined alleles M1 and T1 deficiencies in glutathione-S-transferase genes increases the susceptibility to tacrine hepatotoxicity.

Objectives: Dextromethorphan and chloroguanide (INN, proguanil) are used as prototypic phenotyping substrates of polymorphically expressed CYP2D6 and CYP2C19 in humans. We determined whether the dextromethorphan/dextrorphan and chloroguanide/cycloguanil metabolic ratios, obtained after administration of the parent drugs either alone or in combination, are equivalent., Methods: Thirty-six healthy male volunteers received single oral doses of 80 mg dextromethorphan and 200 mg chloroguanide during a three-period, randomized crossover study. Plasma and urine were collected to calculate metabolic ratios and analyze the disposition kinetics of the probe drugs., Results: All subjects were extensive metabolizers for both CYP2D6 and CYP2C19. Chloroguanide kinetics and urinary metabolic ratio were not altered after dextromethorphan administration. Dextromethorphan urinary metabolic ratio increased from -2.52 +/- 0.67 to -2.03 +/- 0.58 (P < .001) in the presence of chloroguanide. This was caused by an increase of dextromethorphan without a significant change of dextrorphan in both urine and plasma. Inhibition of CYP3A-dependent biotransformation of dextromethorphan to methoxymorphinan did not appear to be responsible for this change because the log(dextromethorphan/methoxymorphinan) urinary ratio, an index of CYP3A activity, did not significantly change during chloroguanide coadministration. The chloroguanide and dextromethorphan metabolic ratio determined from urine collection correlated with the corresponding metabolic ratio determined from plasma obtained 3 hours after oral administration., Conclusion: When CYP2D6 and CYP2C19 activity are assessed, dextromethorphan and chloroguanide cannot be associated in a cocktail because chloroguanide increases the dextromethorphan metabolic ratio. CYP2D6 and CYP2C19 activity can be determined from a blood sample drawn 3 hours after oral administration of dextromethorphan and chloroguanide, respectively.

Objective: To use dynamic electrocardiographic (ECG) techniques to study the influence of heart rate on dofetilide-induced QT prolongation among healthy volunteers., Background: The extent to which heart rate modulates QT prolongation induced by the new class III antiarrhythmic drug dofetilide is a matter of debate., Methods: Ten healthy volunteers underwent two 24-hour ECG recordings, one in the absence of dofetilide and the other after a single oral dose of 0.5 mg dofetilide. Two 4-hour periods were defined during the second recording: Dh, which corresponded to stable high concentration of the drug, and D1, which corresponded to low concentration of the drug. Corresponding baseline recording periods, Ch and C1, matched by time with Dh and D1 were selected from the control ECG recording in the absence of dofetilide. QT versus R-R relations were compared in the presence and absence of dofetilide. The QT versus R-R relation slope was used as an index of the rate dependence QT prolongation. Rate-independent changes in QT duration were also analyzed., Results: During Dh, dofetilide induced a mean 12% lengthening of ventricular repolarization. Dynamic ECG analysis showed that this prolongation increased as R-R cycles became longer, a phenomenon known as reverse rate dependence. However, QT prolongation persisted at the shortest (600 ms) R-R cycle length that could be analyzed. During D1, dynamic ECG analysis showed a persistent, although small, effect of dofetilide on both QT prolongation (3%) and reverse rate dependence of this effect., Conclusions: Dofetilide prolongs QT duration, and this class III effect is influenced by heart rate. Although dofetilide-induced QT prolongation decreases when the R-R cycle shortens, this reverse rate dependence is only partial because marked QT prolongation persists at an R-R cycle of 600 ms. The results of our study indicated that dynamic ECG techniques can be useful in detection of subtle, drug-induced changes in the duration of ventricular repolarization.

Objective: Ivabradine (S-16257) is a new bradycardic agent with a direct effect on the sinus node. Its N-dealkylated metabolite, S-18982, has shown a bradycardic activity in animals. The aim of this trial was to study the correlation between drug bradycardic activity and plasma levels of the parent compound and its metabolite in healthy volunteers., Methods: Eighteen healthy volunteers participated in three successive study periods: an oral double-blind period with two parallel groups of doses (10 or 20 mg, single and repeated); a 10 mg intravenous bolus open period; and a final control period. The effects of ivabradine on heart rate were studied at rest and during bicycle exercise tests (at 85% of maximum workload) during 24-hour postdosing, and ivabradine and S-18982 plasma levels were determined simultaneously., Results: The maximal reductions of exercise heart rate were 11% +/- 4% (10 mg) and 18% +/- 6% (20 mg) after single oral doses (p < 0.05) and 18% +/- 4% (10 mg) and 27% +/- 6% (20 mg) after repeated doses (p < 0.01). Maximum heart rate reduction after the intravenous bolus was 19% +/- 4%. After oral administrations an indirect relationship between the bradycardic effect and the plasma concentrations of the two compounds was found. A pharmacokinetic/pharmacodynamic population analysis done with the NONMEM computer program showed that S-18982 contributes in part to the overall activity of ivabradine: modeling suggested that the metabolite is responsible for the initial bradycardic effect, whereas the parent compound is responsible for the duration of action., Conclusion: This study shows that ivabradine exerts a dose-dependent bradycardic effect and that its N-dealkylated metabolite contributes to this bradycardic effect.

Objective: Tacrine is extensively metabolized by cytochrome P4501A2 (CYP1A2). Fluvoxamine, a potent CYP1A2 inhibitor, may be coadministered with tacrine. The aim of this study was to examine the influence of fluvoxamine administration on the disposition kinetics of single-dose tacrine administration., Methods: Thirteen healthy volunteers participated in this double-blind, randomized crossover study, which compared the effects of fluvoxamine (100 mg/day during 6 days) and placebo on the pharmacokinetics of a single oral dose of tacrine (40 mg)., Results: Fluvoxamine caused a significant increase in tacrine area under the plasma concentration versus time curve (AUC): arythmetic mean, 27 (95% confidence interval [CI], 19 to 38) ng.hr/ml versus 224 (95% CI, 166 to 302) ng. hr/ml. Fluvoxamine caused a decrease in the apparent oral clearance of tacrine from 1683 +/- 802 to 200 +/- 106 L/hr (mean +/- SD), which was explained by a decrease in its nonrenal clearance. Five subjects had gastrointestinal side effects during fluvoxamine administration. Fluvoxamine administration was associated with significant increases in the plasma AUC values of three monohydroxylated tacrine metabolites and in the total urinary recovery measurements of tacrine and its metabolites (9.1% +/- 4.6% versus 24.0% +/- 2.6% of recovery). These results may be attributable to fluvoxamine-dependent inhibition of CYP1A/, which is responsible of the biotransformation of tacrine into its monohydroxylated metabolites and further into dihydroxylated and reactive metabolites., Conclusion: Fluvoxamine inhibits the metabolism of tacrine. CYP1A2 may be the target of this inhibition. Fluvoxamine may modulate the hepatotoxicity of tacrine, depending on the relative contribution of tacrine and its reactive metabolites to this toxicity.

Objectives: To examine whether the variability of CYP2D6 activity in patients with chronic renal failure can be assessed, particularly among subjects with the extensive metabolizer phenotype, by use of standard in vivo indexes of CYP2D6 activity derived from oral administration of dextromethorphan and sparteine., Methods: A single 100 mg oral dose of sparteine and a single 40 mg oral dose of dextromethorphan were administered on two occasions to 12 patients with chronic renal failure (creatinine clearance ranging from 20 to 70 ml/min) and 12 age- and sex-matched healthy subjects. Sparteine clearances, sparteine metabolic ratio, and urinary recovery of dextrorphan were calculated. Patients and healthy control subjects were not selected on the basis of their CYP2D6 phenotypes., Results: Chronic renal failure was associated with a decrease in sparteine partial metabolic clearance to dehydrosparteine (median of 322 ml/min and range of 62 to 670 ml/min in patients with renal failure versus median of 635 ml/min and range of 77 to 1276 ml/min in normal subjects; p < 0.02). Sparteine apparent oral clearance (p < 0.03) and renal clearance (p < 0.001) decreased in patients with renal failure. However, sparteine metabolic ratio was not significantly altered in patients with renal failure and showed that all patients were extensive metabolizers of sparteine. Although fractional urinary excretion of dextrorphan decreased in patients with renal failure (median, 24.4%; range, 9.7% to 55.9%) compared with control (median, 47.5%; range, 24.1% to 72.1%) (p = 0.02), it also showed that all subjects were extensive metabolizers of dextromethorphan. The amount of dextromethorphan excreted in urine correlated with creatinine clearance independently from CYP2D6 activity measured as sparteine partial metabolic clearance. However, it did not correlate with sparteine metabolic ratio or with fractional urinary excretion of dehydrosparteine., Conclusion: Assessment of CYP2D6 activity by use of dextromethorphan and sparteine is possible in extensive metabolizer patients with chronic renal failure. However, in these subjects, dextromethorphan and sparteine do not reflect CYP2D6 activity in the same way.

Objectives: The main objective of this study was to examine the relations between chloroguanide (proguanil) and mephenytoin metabolic ratios to determine whether or not chloroguanide could replace mephenytoin as a probe for the indirect in vivo measurement of CYP2C19 activity. An additional objective was to examine the interactions between chloroguanide, omeprazole, and mephenytoin, which are three substrates of CYP2C19., Methods: Twenty healthy volunteers received 200 mg chloroguanide orally on three separate occasions in an open, randomized-sequence crossover design: once alone, once 2 hours before the oral administration of 100 mg mephenytoin, and once after oral administration for 7 days of 40 mg/day omeprazole. During one additional period, 100 mg mephenytoin was administered orally. The chloroguanide to cycloguanil ratio was determined in plasma 4 hours after drug administration; it was determined in urine collected over 4, 8, and 24 hours. The mephenytoin hydroxylation index was also measured in urine., Results: All subjects were extensive metabolizers of chloroguanide and mephenytoin. We found no correlation between the mephenytoin hydroxylation index and the chloroguanide to cycloguanil ratio in any of the urine samples collected or in plasma. In the presence of chloroguanide, mephenytoin hydroxylation index increased from a baseline value of 1.2 +/- 0.2 to 1.7 +/- 1.0 (p < 0.05). In the presence of omeprazole, the chloroguanide to cycloguanil metabolic ratio in 24-hour urine increased from 2.2 +/- 1.0 to 5.6 +/- 3.2 (p < 0.001)., Conclusion: Chloroguanide inhibits the CYP2C19-dependent 4'-hydroxylation of mephenytoin. The bioactivation of chloroguanide to cycloguanil is inhibited by the CYP2C19 substrate omeprazole. However, the chloroguanide to cycloguanil metabolic ratio does not reflect the same array of S-mephenytoin hydroxylase activities found in extensive metabolizers as that show by the mephenytoin hydroxylation index.

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.

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.

We studied the influence of cytochrome P450 2D6 (CYP2D6) on the steady-state disposition kinetics and the electrocardiographic effects of flecainide at two doses and during combination with amiodarone. Seven extensive and five poor metabolizers of dextromethorphan were studied during a three-period crossover study. All subjects received 50 mg flecainide every 12 hours, alone or together with 200 mg amiodarone every 12 hours, and 100 mg flecainide every 12 hours for 5 days. Mean steady-state plasma concentration of flecainide and QRS change from predrug value did not differ significantly among extensive and poor metabolizer subjects during each study period. Except for a shortened elimination half-life and nonlinear kinetics in extensive metabolizer subjects, phenotype had no significant influence on flecainide pharmacokinetics. Combination with amiodarone resulted in an increase in mean flecainide plasma concentration and effect in subjects with both phenotypes. Our findings indicate that CYP2D6 phenotype predicts flecainide nonlinear kinetics and flecainide half-life but has no influence on electrocardiographic effects during repeated administration of flecainide or on the extent of the amiodarone-flecainide interaction.

d-Sotalol was developed as an antiarrhythmic agent with a relative lack of antagonist activity at beta-adrenergic receptors. Exercise heart rate reduction has been observed after administration to humans. The purpose of this study was to determine directly whether this effect of d-sotalol was attributable to beta-blockade. Plasma samples from normal volunteers who randomly received either atenolol, d-sotalol, or placebo were used in an in vitro radioreceptor assay to determine occupancy of beta 1-adrenergic receptors by antagonist present in the plasma. Occupancy was compared with the observed pharmacologic effects. A reduction in exercise heart rate of 7.7% +/- 3.8% for d-sotalol and 15.9% +/- 3.0% for atenolol occurred with beta 1-adrenergic receptor occupancy of 0% and 33.9% +/- 21.4%, respectively. Absence of antagonist effect in the radioreceptor assay eliminates the potential role of beta 1-blockade in d-sotalol-induced heart rate reduction. This effect is most likely a result of prolongation of the sinus node action potential duration.

We examined the influence of toloxatone, a new reversible monoamine oxidase-A inhibitor used in the treatment of depression, on tyramine-induced pressor effect in healthy volunteers. The maximum increase in systolic blood pressure produced by four single oral doses of tyramine administered during a meal and ranging from 100 mg to 800 mg was compared during repeated (3 to 5 days) administration of placebo, 200 mg toloxatone three times a day and 400 mg toloxatone three times a day in a single-blind, three-period crossover study. Toloxatone by itself had no significant influence on blood pressure. During administration of toloxatone, no significant increase in tyramine-induced increase in systolic blood pressure was observed for tyramine doses of 200 mg or less that are consistently higher than those associated with normal food intake. However, toloxatone increased the tyramine-induced increase in blood pressure after 400 mg tyramine (400 mg toloxatone three times a day) and 800 mg tyramine (200 mg toloxatone three times a day and 400 mg toloxatone three times a day). This pharmacodynamic interaction could be explained by an increase in tyramine systemic bioavailability in the presence of toloxatone. It is concluded that interaction between tyramine in meals and toloxatone is unlikely to occur in patients after long-term administration of the drug at therapeutic dosages.

The relationship between racemic sotalol plasma concentrations and QTc interval prolongation after both single-dose and repeated administration of three sotalol oral doses was studied in a randomized crossover protocol performed in 10 healthy volunteers. QTc interval increase was significant after the three single-dose sotalol administrations and was significantly related to the administered dose (p < 0.0001). In 21 of 30 analyses, QTc interval was linearly correlated with sotalol plasma concentrations. After the 320 mg dose, the linear model was a best fit for 90% of the cases, and no hysteresis was observed. After repeated sotalol administration, 69 of 87 QTc interval measurements at steady state could be predicted from the plasma concentration versus effect relationship established after single-dose 320 mg administration. Seventeen of 18 errors (94%) corresponded to QTc intervals that were significantly lower than predicted. These findings suggest that a short-term individual linear model determined after a 320 mg test dose of sotalol allows a good prediction of expected maximal increase in QTc duration in healthy subjects.

It has been suggested recently that the bioactivation of chloroguanide hydrochloride (proguanil) to its active antimalarial metabolite cycloguanil cosegregates with the genetically determined polymorphism of mephenytoin hydroxylation. We determined the chloroguanide to cycloguanil ratio in urine after oral administration of a single dose of 200 mg proguanil either alone or together with 100 mg racemic mephenytoin or 40 mg dextromethorphan in a randomized crossover study performed in 24 healthy subjects. The mephenytoin hydroxylation index was also determined after administration of 100 mg racemic mephenytoin either alone or together with 200 mg proguanil. Two subjects were poor metabolizers and one subject was an intermediate metabolizer of mephenytoin. These three subjects had chloroguanide to cycloguanil ratios of more than 50. The 21 subjects with the extensive metabolizer phenotype for mephenytoin hydroxylation had chloroguanide to cycloguanil ratios of less than 10. The chloroguanide to cycloguanil ratio was not significantly altered by mephenytoin or dextromethorphan coadministration. The trend toward a correlation between chloroguanide/cycloguanil ratio and log mephenytoin hydroxylation index did not reach statistical significance. Inclusion of the dextromethorphan metabolic ratio into the model did not improve the relationship. These findings confirm that the bioactivation of chloroguanide to cycloguanil cosegregates with the genetically determined activity of the CYP2C family. However, the chloroguanide to cycloguanil ratio and the mephenytoin hydroxylation index do not similarly reflect the variable activity of CYP2C.

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)

Encainide metabolism is mediated by the polymorphically distributed cytochrome P450IID6, which displays stereoselectivity for some substrates. In this study we found that urinary recovery during steady-state encainide in three poor metabolizers was high (49% to 80%), consisted mainly of unchanged encainide, was nonstereoselective (+/- ratio, 0.985 to 1.049), and was unchanged by quinidine, a potent inhibitor of P450IID6. In contrast, in seven extensive metabolizers the +/- urinary ratios were 1.20 +/- 0.06 for encainide and 0.81 +/- 0.06 (both p less than 0.01) for the cytochrome P450IID6 products O-desmethylencainide plus 3-methoxy-O-desmethylencainide; with quinidine the total percentage recovery rose from 4% +/- 4% to 37% +/- 9% because of increased recovery of unchanged encainide and became non-stereoselective (+/- ratio, 0.84 +/- 0.08 [encainide alone] versus 0.97 +/- 0.05 [encainide plus quinidine]). In vitro, encainide enantiomers depressed the maximum rate of metabolism with similar frequency and concentration dependence. We conclude that (-)-encainide undergoes preferential metabolism by cytochrome P450IID6; however, this genetically determined stereoselective disposition is unlikely to play a major role in mediating the clinical actions of encainide.

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.

Food has been shown to reduce the bioavailability of the angiotensin-converting enzyme inhibitor captopril, but not the bioavailability of inhibitors administered as ester prodrugs. Perindopril is the ester pro-drug of the angiotensin-converting enzyme inhibitor perindoprilat. The influence of food on the pharmacokinetics of perindopril (4 mg administered orally) and the time course of angiotensin-converting enzyme inhibition in serum was studied in a randomized crossover short-term study of 12 healthy subjects. Food significantly decreased the relative availability of perindoprilat by 35% +/- 42%, the fractional urinary excretion of perindoprilat from 19% +/- 7% to 13% +/- 4% (p less than 0.05), and the partial metabolic clearance of perindopril to perindoprilat from 102 +/- 57 ml.min-1 to 72 +/- 32 ml.min-1 (p less than 0.05). These changes were associated with a significant decrease in the area under the percent angiotensin-converting enzyme inhibition-versus-time curve by 15% (p less than 0.05). Food did not alter the total amount of drug recovered in urine as perindopril and its metabolites, and it did not alter perindoprilat renal clearance. We concluded that food alters the conversion of perindopril to its active metabolite perindoprilat after single-dose administration of perindopril.

Recainam, a new antiarrhythmic drug, was evaluated in 20 patients with drug-resistant stable ventricular arrhythmias. Dosage was increased stepwise every 48 to 72 hours until arrhythmia suppression, side effects, or a predetermined maximal dosage occurred. After a pharmacokinetic evaluation, efficacy was confirmed in a double-blind, crossover protocol. One patient had unusable ambulatory ECG data. There were 14 of 19 patients who responded during dose titration; efficacy was confirmed in 11 of 14. The mean effective dosage and trough plasma concentration were 427 mg every 8 hours and 1.83 micrograms/ml, respectively. One patient withdrew because of nausea. Slowing of intraventricular conduction necessitated dosage reduction in two patients. Plasma half-life was 9.4 +/- 4.1 hours, with renal elimination accounting for 62% of oral clearance. However, 66% of the variability in oral drug clearance was the result of nonrenal elimination. Oral recainam at dosages of 300 to 600 mg every 8 hours is effective in some drug-resistant ventricular arrhythmias and is well tolerated.