Jaya Natarajan

Effects of three fluoroquinolones on QT interval in healthy adults after single doses

A clinical trial was conducted in healthy adult volunteers to assess the effect of levofloxacin, moxifloxacin, and ciprofloxacin on the QT and QTc interval.

Pharmacokinetic overview of Ortho Evra™/Evra™

OBJECTIVE The pharmacokinetics of norelgestromin, the primary active metabolite of norgestimate, plus ethinyl estradiol (EE), delivered by the once-weekly contraceptive patch (Ortho Evra/Evra), have been studied in eight trials. This overview summarizes the relevant pharmacokinetic data for the contraceptive patch. DESIGN Review article. RESULT(S) The amount of norelgestromin and EE absorbed from the patch is proportional to patch size: the 20-cm(2) patch (Ortho Evra) delivers norelgestromin, 150 microg/d, and EE, 20 microg/d, to the systemic circulation. After single and multiple applications of the contraceptive patch, daily serum concentrations (area under the serum concentration-versus-time curve) of norelgestromin and EE were within the ranges generally seen with oral norgestimate, 250 microg/EE 35 microg (Ortho-Cyclen/Cilest), but without the peaks and troughs characteristic of oral dosing. Moreover, the contraceptive patch maintains serum concentrations of norelgestromin and EE within these ranges for up to 10 days, suggesting that clinical efficacy would be maintained even if a scheduled change is missed for as long as two full days. Regardless of the location of patch application (abdomen, buttock, upper outer arm, or torso [excluding breasts]) and even under conditions of heat, humidity, exercise, and cool-water immersion, efficacious concentrations of norelgestromin and EE are achieved. Coadministration of the patch with tetracycline did not affect the pharmacokinetics of norelgestromin and EE. CONCLUSION(S) The contraceptive patch exhibits an excellent pharmacokinetic profile, maintaining efficacious serum hormone concentrations under varying conditions.

Safety and Pharmacokinetics of Multiple 750-Milligram Doses of Intravenous Levofloxacin in Healthy Volunteers

ABSTRACT The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation.

Levofloxacin pharmacokinetics in children.

Levofloxacin is a broad‐spectrum fluoroquinolone antibiotic with activity against many pathogens that cause bacterial infections in children, including penicillin‐resistant pneumococci. To provide dosing guidance for children, 3 single‐dose, multicenter pharmacokinetic studies were conducted in 85 children in 5 age groups: 6 months to <2 years, 2 to <5 years, 5 to<10 years, 10 to <12 years, and 12 to 16 years. Each child received a single 7‐mg/kg dose of levofloxacin (not to exceed 500 mg) intravenously or orally. Plasma and urine samples were collected through 24 hours after dose. Pharmacokinetic parameters were estimated and compared among the 5 age groups and to previously collected adult data. Levofloxacin absorption (as indicated by Cmax and tmax) and distribution in children are not age dependent and are comparable to those in adults. Levofloxacin elimination (reflected by t1/2 and clearance), however, is age dependent. Children younger than 5 years of age clear levofloxacin nearly twice as fast (intravenous dose, 0.32 ± 0.08 L/h/kg; oral dose, 0.28 ± 0.05 L/h/kg) as adults and, as a result, have the total systemic exposure (area under the plasma drug concentration‐time curve) approximately one half that of adults. The levofloxacin area under the plasma drug concentration‐time curve (dose normalized) in children receiving a single dose of the oral liquid formulation is comparable to that in children receiving the intravenous formulation. To provide compatible levofloxacin exposures associated with clinical effectiveness and safety in adults, children <5 years need a daily dose of 10 mg/kg, whereas children 6 months to <5 years should receive 10 mg/kg every 12 hours.

Pharmacokinetics of Norelgestromin and Ethinyl Estradiol Delivered by a Contraceptive Patch (Ortho Evra™/Evra™) under Conditions of Heat, Humidity, and Exercise

The objectives of this randomized, open‐label, three‐period, incomplete block design study were to evaluate the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE) delivered by the contraceptive patch, Ortho EvraTM/EvraTM, and to evaluate patch adhesion under conditions of heat, humidity, and exercise. During each treatment period, 30 healthy women wore Ortho EvraTM on the abdomen for 7 days under one of six conditions (normal activity, sauna, whirlpool, treadmill, cool water immersion, ora combination of activities). Blood samples were collected before and several times to 240 hours after patch application. Mean serum concentrations of NGMN and EE generally remained within the reference ranges, 0.6 to 1.2 ng/ml and 25 to 75 pg/ml, respectively, duringthe 7‐day wear period for all activities. Only 1 (1.1%) of 87 patches completely detached spontaneously. Peel force measurements were comparable for all activities. Ortho EvraTM was well tolerated. In conclusion, Ortho EvraTM delivers efficacious concentrations of NGMN and EE and maintains adhesive reliability through 7 days of wear even under conditions of heat, humidity, and exercise.

Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants.

This open-label, randomized study evaluated the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE) following the application of a contraceptive patch (1/week) for three cycles (3 weeks/cycle). Healthy women (n = 24) wore a 20-cm(2) patch (ORTHO EVRA/EVRA) on either their abdomen or buttock during blood sampling weeks and on any of four approved sites at other times. Serum was analyzed for NGMN and EE from samples taken during Week 1 of Cycle 1 and Weeks 1-3 of Cycle 3. Steady-state conditions were achieved during the three-cycle study. The patch delivered NGMN and EE at steady-state concentrations within their reference ranges throughout three cycles of treatment; reference ranges are based on studies with ORTHO-CYCLEN/Cilest. Steady-state serum concentrations and area under the curve from 0 to 168 h increased only slightly from Cycle 1, Week 1 to Cycle 3, Week 3 for NGMN and EE, indicating minimal accumulation. Treatment was well tolerated, and patch adhesion was excellent.

Measuring the Effects of Supratherapeutic Doses of Levofloxacin on Healthy Volunteers Using Four Methods of QT Correction and Periodic and Continuous ECG Recordings

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 drugs 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.

Pharmacokinetics, Safety, and Tolerability of Doripenem After 0.5‐, 1‐, and 4‐Hour Infusions in Healthy Volunteers

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.

Absence of a Pharmacokinetic Interaction Between Intravenous Theophylline and Orally Administered Levofloxacin

A randomized, placebo‐controlled, two‐way crossover study in 16 healthy men was performed to determine the effect of orally administered levofloxacin at steady‐state conditions, given at 500 mg every 12 hours, on the pharmacokinetics of theophylline given as a single 4.5‐mg/kg intravenous infusion. Participants were assigned randomly to receive theophylline with levofloxacin in one study period and theophylline with placebo in the other period. Fourteen individuals completed the study. Mean (± SD) values for theophylline pharmacokinetic parameters for the levofloxacin and placebo treatments, respectively, were peak plasma concentrations (Cmax) of 11.4 (1.8) μg/mL and 10.7 (1.3) μg/mL; areas under the concentration time curve from time 0 extrapolated to infinity (AUC0‐∞) of 124 (32) μg · hr/mL and 126 (30) μg · hr/mL; volumes of distribution at steady state (Vdss) 31.7 (3.5) L and 32.0 (3.9) L; clearances (Cl) of 48.6 (11.6) mL/min and 47.4 (10.3) mL/min; and half‐lives (t1/2) of 8.1 (1.9) hours and 8.2 (1.8) hours. There were no statistically significant differences between treatments for any of these parameters. There was no pharmacokinetic interaction between levofloxacin administered orally at steady‐state conditions and intravenously administered theophylline.

Randomized 5‐Treatment Crossover Study to Assess the Effects of External Heat on Serum Fentanyl Concentrations During Treatment With Transdermal Fentanyl Systems

This randomized, open‐label, 5‐treatment, 5‐sequence crossover study was designed to evaluate the effects of a heating pad on serum fentanyl concentrations with reservoir and matrix transdermal fentanyl systems. Subjects were randomized to 1 of 5 treatment sequences, receiving 5 fentanyl treatments (1 per period) for 36 hours: 25 μg/h reservoir without heat, 25 μg/h reservoir with heat, 25 μg/h matrix without heat, 25 μg/h matrix with heat, and a 50 μg/h reservoir without heat. The 25 μg/h systems with heat had a heating pad applied from 0 to 10 and 26 to 36 hours post application. Washout periods between treatments were 5 to 14 days. Naltrexone was given to block the opioid effects of fentanyl. Study results indicate that external heat had a similar effect on both matrix and reservoir systems, with heat applied during the first 10 hours of treatment increasing fentanyl exposure by approximately 61% to 81% at 10 hours (observed serum concentration at 10 hours) and overall exposure (area under the curve from 0 to 10 hours) by approximately 120% to 184%, but had minimal effect from 26 to 36 hours. The increased exposure observed with heat in both 25 μg/h systems, between 0 and 10 hours, was higher than that obtained with the 50 μg/h reservoir system applied without heat.