The pharmacokinetics, safety, and tolerability of doripenem in healthy subjects were evaluated in 2 studies. Study 1 was a double-blind, randomized, placebo-controlled dose-escalation study in which doripenem was administered for 7 days by infusion over 30 minutes (500 mg) or 1 hour (1000 mg). Study 2 was an open-label, randomized, 3-way crossover study in which each subject received a single dose of each of the following doripenem treatments on separate occasions: 500 mg infused over 1 hour, 500 mg infused over 4 hours, and 1000 mg infused over 4 hours. Doripenem exhibited linear pharmacokinetics with concordance between the studies for pharmacokinetic parameters. Doripenem did not accumulate with repeated dosing over 7 days. The area under the plasma concentration-time curve (AUC) for doripenem 500 mg infused over 1 hour versus 4 hours was bioequivalent, and the AUC and Cmax increased proportionally with dose for the 500- and 1000-mg doses administered over 4 hours. These results, along with the stability profile of doripenem, support its use as a prolonged infusion. All regimens of doripenem were safe and well tolerated.
A clinical trial was conducted in healthy volunteers using both periodic and continuous ECG recordings to assess the effect of increasing doses of levofloxacin on the QT and QTc interval. Periodic and continuous ECGs were recorded before and after subjects were dosed with placebo and increasing doses of levofloxacin (500 mg, 1000 mg, 1500 mg) that included doses twice the maximum recommended dose of 750 mg in a double-blind, randomized, four-period, four-sequence crossover trial. Mean heart rate (HR) and the QT and QTc interval after dosing with levofloxacin and placebo were compared, and HR-QT interval relationships defined by linear regression analysis were calculated. After single doses of 1000 and 1500 mg of levofloxacin, HR increased significantly, as measured by periodic and continuous ECG recordings. This transient increase occurred at times of peak plasma concentration and was without symptoms. Mean QT intervals after placebo and mean intervals after levofloxacin were indistinguishable. Using periodic ECG recordings, single doses of 1500 mg were associated with small increases in QTc that were statistically significant. In contrast, an effect on QTc was shown only using the Bazett formula with data obtained from continuous ECG recordings. Together with the finding that levofloxacin does not influence HR-QT relationships, these findings suggest that levofloxacin has little effect on prolonging ventricular repolarization and that small increases in HR associated with high doses of levofloxacin contribute to the drug's apparent effect on QTc. Single doses of 1000 or 1500 mg of levofloxacin transiently increase HR without affecting the uncorrected QT interval. Differences in mean QTc after levofloxacin compared to placebo vary depending on the correction formula used and whether the data analyzed are from periodic or continuous ECG recordings. This work suggests that using continuous ECG recordings in assessing QT/QTc effects of drugs may be of value, particularly with drugs that might influence HR.
Domperidone effects on QTc duration were assessed in a single-center, double-blind, four-way crossover study of 44 healthy participants randomized to one of four treatment sequences consisting of four treatment periods separated by 4–9 days washout. On Day 1 of each 4-day period, participants began oral domperidone 10 or 20 mg q.i.d., matching placebo q.i.d., or single-dose moxifloxacin 400 mg (positive control)/placebo q.i.d. In each period, triplicate 12-lead electrocardiograms were recorded at baseline (30, 20, and 10 minutes predose), 8 timepoints after dosing on Days 1 and 4, and predose on Day 4. In mixed effects models, the largest difference for domperidone in least squares means for change from baseline QTcP versus placebo was 3.4 milliseconds (20 mg q.i.d., Day 4), 90% CI: 1.0–5.9, and <10 milliseconds at all timepoints for both domperidone dosages. Moxifloxacin response confirmed assay sensitivity. Participants achieved expected domperidone plasma exposures. No significant exposure-response relationship was found for QTc increase per ng/mL domperidone (90% CI of the slope estimate included zero at mean Cmax on Day 1 or Day 4). In summary, domperidone at doses up to 80 mg/day did not cause clinically relevant QTc interval prolongation.
O-glucuronidation is the major metabolic elimination pathway for canagliflozin. The objective was to identify enzymes and tissues involved in the formation of 2 major glucuronidated metabolites (M7 and M5) of canagliflozin and subsequently to assess the impact of genetic variations in these uridine diphosphate glucuronosyltransferases (UGTs) on in vivo pharmacokinetics in humans. In vitro incubations with recombinant UGTs revealed involvement of UGT1A9 and UGT2B4 in the formation of M7 and M5, respectively. Although M7 and M5 were formed in liver microsomes, only M7 was formed in kidney microsomes. Participants from 7 phase 1 studies were pooled for pharmacogenomic analyses. A total of 134 participants (mean age, 41 years; men, 63%; white, 84%) were included in the analysis. In UGT1A9*3 carriers, exposure of plasma canagliflozin (Cmax,ss , 11%; AUCτ,ss , 45%) increased relative to the wild type. An increase in exposure of plasma canagliflozin (Cmax,ss , 21%; AUCt,ss , 18%) was observed in participants with UGT2B4*2 genotype compared with UGT2B4*2 noncarriers. Metabolites further delineate the role of both enzymes. The pharmacokinetic findings in participants carrying the UGT1A9*3 and UGT2B4*2 allele implicate that UGT1A9 and UGT2B4 are involved in the metabolism of canagliflozin to M7 and M5, respectively.
In these combined analyzes from 3 open-label, phase-1 studies, the pharmacokinetic profile of tramadol and its metabolite (M1) following administration of tramadol immediate-release (IR) tablets in children and adolescents, 7-16 years old (studies 1 and 2: n = 38; study 3: n = 21) with painful conditions following single oral dose of tramadol IR (25-100 mg) (studies 1 and 2) or multiple oral doses of tramadol IR tablets every 6 hours for 3 days (study 3) were compared with that of healthy adults following similar treatment. Area under the curve of tramadol and its metabolite M1 in children and adolescents was lower compared with adults (Dose-normalized [DN] AUC, h ng/mL: tramadol: 1316.87 [children]; 1418.02 [adolescents];1838.29 [adults]; M1: 342.56 [children]; 475.4 [adolescents]; 636.13 [adults]) while the Cmax remained similar (DN Cmax , ng/mL: tramadol: 203.75 [children]; 165.35 [adolescents]; 226.92 [adults]; M1: 34.93 [children]; 38.42 [adolescents]; 52.14 [adults]). The DN AUC was further lower in children and adolescents with a lower body weight (<50 kg). The weight normalized oral clearance of tramadol was higher in children and adolescents compared with adults (CL/F, mL/min/kg: 12.66 [children]; 11.75 [adolescents]; 9.06 [adults]). No new safety findings emerged. Tramadol was generally safe and well-tolerated by children and adolescents with painful conditions.
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