Nancy K. Hopkins

Pharmacokinetics of Linezolid in Subjects with Renal Dysfunction

ABSTRACT Linezolid is a member of a new, unique class of synthetic antibacterial agents called oxazolidinones that are effective against gram-positive bacteria, including vancomycin-resistant organisms. We tested the hypothesis that the linezolid clearance would not be altered in subjects with renal dysfunction. Twenty-four subjects with renal function that ranged from normal to severe chronic impairment were enrolled, including patients with end-stage renal disease who were maintained on hemodialysis. Hemodialysis subjects were studied while they were both on and off dialysis. Linezolid was administered as a single oral 600-mg dose, and plasma and urine samples were assayed for linezolid and metabolites for 48 h for all subjects and for up to 96 h for those subjects with impaired renal function not on dialysis. The total apparent oral clearance of linezolid did not change with renal function and ranged from 92.5 to 109.6 ml/min for subjects not requiring dialysis. For subjects on dialysis, the total apparent oral clearance increased from 76.6 ml/min on their off-dialysis day to 130.0 ml/min on their on-dialysis day. Approximately one-third of the dose was removed by dialysis. However, those subjects with severe renal insufficiency (creatinine clearance, <40 ml/min) and those with end-stage renal disease maintained on hemodialysis had higher concentrations of both metabolites. We conclude that no adjustment of the linezolid dosage is needed in subjects with renal dysfunction or subjects on hemodialysis.

Linezolid pharmacokinetics in pediatric patients: an overview.

Background. There are a number of physiologic and developmental differences between children and adults that can influence the absorption, distribution, metabolism and elimination of a drug. Therefore it is important to determine the specific pharmacokinetic characteristics for individual drugs in pediatric patients so that appropriate age-specific dosage regimens can be developed and evaluated in clinical trials. This review summarizes the pharmacokinetic parameters of linezolid in pediatric patients and the rationale for the approved dosing recommendations for this population. Methods. The pharmacokinetics of linezolid in pediatric patients has been evaluated in 4 clinical trials, including >180 patients ranging in age from preterm newborn infants up to 18 years of age. In all of these studies, patients received a single intravenous dose of linezolid. Plasma linezolid concentrations have been determined by validated high performance liquid chromatography (adult studies) or liquid chromatography/mass spectrometry/mass spectrometry (pediatric studies) methods. Results. The pharmacokinetics of linezolid, especially elimination clearance, is age-dependent. Children younger than 12 years of age have a smaller area under the drug concentration-time curve, a faster clearance and a shorter elimination half-life than adults. Although clearance rates in newborn infants are similar to those in adults, clearance increases rapidly during the first week of life, becoming 2- to 3-fold higher than in adults by the seventh day of life. The clearance of linezolid decreases gradually among young children, becoming similar to adult values by adolescence. The pharmacokinetics of linezolid in children age 12 years and older is not significantly different from that of adults. Conclusions. Because of the higher clearance and lower area under the drug concentration-time curve, a shorter dosing interval for linezolid is required for children younger than 12 years of age to produce adequate drug exposure against target Gram-positive pathogens.

Linezolid: Pharmacokinetic and Pharmacodynamic Evaluation of Coadministration with Pseudoephedrine HCl, Phenylpropanolamine HCl, and Dextromethorphan HBr

Linezolid is a novel oxazolidinone antibiotic with mild reversible monoamine oxidase inhibitor (MAOI) activity. The potential for interaction with over‐the‐counter (OTC) medications requires quantification. The authors present data evaluating the pharmacokinetic and pharmacodynamic responses to coadministration of oral linezolid with sympathomimetics (pseudoephedrine and phenylpropanolamine) and a serotonin reuptake inhibitor (dextromethorphan). Following coadministration with linezolid, minimal but statistically significant increases were observed in pseudoephedrine and phenylpropanolamine plasma concentrations; a minimal but statistically significant decrease was observed in dextrorphan (the primary metabolite of dextromethorphan) plasma concentrations. Increased blood pressure (BP) was observed following the coadministration of linezolid with either pseudoephedrine or phenylpropanolamine; no significant effects were observed with dextromethorphan. None of these coadministered drugs had a significant effect on linezolid pharmacokinetics. Minimal numbers of adverse events were reported. Potentiation of sympathomimetic activity by linezolid was judged not to be clinically significant, but patients sensitive to the effects of increased BP due to predisposing factors should be treated cautiously. No restrictions are indicated for the coadministration of dextromethorphan and linezolid.

Linezolid, a novel oxazolidinone antibiotic: assessment of monoamine oxidase inhibition using pressor response to oral tyramine.

The primary objective of this study was to compare the effects of oral linezolid with moclobemide and placebo on the pressor response to oral tyramine. Secondary objectives were to determine possible mechanisms of the effect based on changes in the pharmacokinetics of tyramine and to evaluate alternative methods for quantifying the pressor effect. Subjects received linezolid (625 mg bid orally), moclobemide (150 mg tid orally), or placebo for up to 7 days. Using the oral tyramine dose producing a > 30 mmHg increase in systolic blood pressure (SBP) (PD>30), a positive pressor response was defined as a PD> 30 index (pretreatment/treatment ratio of PD> 30) of ≥ 2. There were 8/10, 11/11, and 1/10 responders with linezolid, moclobemide, and placebo, respectively. Responses returned to baseline within 2 days of drug discontinuation. The ratio of mean greatest SBP and heart rate at the time of greatest SBP (GSBP/HR) increased linearly with tyramine dose both pretreatment and during treatment with linezolid and moclobemide. During treatment, responses to tyramine when subjects took linezolid or moclobemide were significantly different from placebo. Both drugs significantly decreased tyramine oral clearance compared with placebo. Urinary excretion of catecholamines and metabolites was consistent with MAOI activity of the drugs, but results were variable. The MAOI activity of linezolid is similar to that of moclobemide, a drug used clinically without food restrictions. Restrictions to normal dietary intake of tyramine‐containing foods are not warranted when taking linezolid.

Impact of ontogeny on linezolid disposition in neonates and infants

The impact of age on linezolid disposition during the first few months of life has not been previously investigated. We characterized linezolid pharmacokinetics after a single, 10.0‐mg/kg intravenous dose in 42 infants stratifiedas follows: group 1 (n = 9), gestational age <34 weeks and postnatal age <8 days; group 2 (n = 7), gestationalage <34 weeks and postnatal age 8 days to 12 weeks; group 3 (n = 11), gestational age ≥34 weeks and postnatal age <8 days; and group 4 (n = 15), gestational age ≥34 weeks and postnatal age 8 days to 12 weeks. Linezolid was quantitated by a validated HPLC–triple‐quadrupole mass spectrometer method from repeated blood samples (n =7, 0.3 mL each) obtained over a 12‐hour period. Pharmacokinetic parameters were determined by standard model‐dependent techniques. The values (mean ± SD) for total body clearance (CL) (0.25 ± 0.12 L · h−1 · kg−1), apparent volume of distribution (VDss) (0.75 ± 0.19 L/kg), and elimination half‐life (t1/2) (2.8 ± 2.1 hours) from the entire study cohort were similar to values reported previously for children and adolescents. Examination of the linezolid pharmacokinetics as a function of age revealed that CL increased rapidly during the first week of life and as a function of postnatal age. Age stratification revealed lower values for CL in those infants aged less than 8 days (group 1, 0.12 ± 0.06 L · h−1 · kg−1; group 3, 0.23 ± 0.12 L · h−1 · kg−1) as compared with those aged 8 days to 12 weeks (group 2, 0.31 ± 0.07 L · h−1 · kg−1; group 4, 0.31 ± 0.10 L · h−1 · kg−1). In contrast to the results for CL, gestational age served to be the most useful predictor of VDss. Evaluation of the pharmacokinetic data would appear to support the use of linezolid dosing regimens currently approved for infants and young children in neonates with postnatal age greater than 7 days.

A Pharmacokinetic Evaluation of Concomitant Administration of Linezolid and Aztreonam

Linezolid, a new oxazolidinone antimicrobial agent, has a spectrum of activity encompassing a wide variety of Gram‐positive bacteria. The purpose of this study was to evaluate the pharmacokinetics of linezolid and aztreonam, an antimicrobial agent with selective activity against Gram‐negative bacteria, when given alone and in combination. Healthy subjects were randomized to receive single, 30‐minute intravenous infusions of (1) linezolid 375 mg, (2) aztreonam 1000 mg, and (3) linezolid 375 mg plus aztreonam 1000 mg in an open‐label, crossover manner. The only statistically significant differences observed with combination treatment relative to each drug alone were an increase in the maximum plasma concentration of linezolid (∼18%) and an approximate 7% decrease in the apparent elimination rate of aztreonam, neither of which are expected to be clinically significant. In healthy subjects, the combination of linezolid and aztreonam was safe and well tolerated compared with each agent used alone. Pharmacokinetic data demonstrate that coadministration of linezolid and aztreonam does not alter the disposition of either agent under single‐dose conditions. Therefore, it is not expected that a dose alteration of either agent will be necessary in a clinical setting.

Hormonal Effects on Tirilazad Clearance in Women: Assessment of the Role of CYP3A

This study assessed whether the previously reported difference in tirilazad clearance between pre‐ and postmenopausal women is reversed by hormone replacement and whether this observation can be explained by differences in CYP3A4 activity. Ten healthy women from each group were enrolled: premenopausal (ages 18–35), postmenopausal (ages 50–70), postmenopausal receiving estrogen, and postmenopausal women receiving estrogen and progestin. Volunteers received 0.0145 mg/kg midazolam and 3.0 mg/kg tirilazad mesylate intravenously on separate days. Plasma tirilazad and midazolam were measured by HPLC/dual mass spectrophotometry (MS/MS) assays. Tirilazad clearance was significantly higher in premenopausal women (0.51 ± 0.09 L/hr/kg) than in postmenopausal groups (0.34 ± 0.07, 0.32 ± 0.06, and 0.36 ± 0.08 L/hr/kg, respectively) (p = 0.0001). Midazolam clearance (0.64 ± 0.12 L/hr/kg) was significantly higher in premenopausal women compared to postmenopausal groups (0.47 ± 0.11, 0.49 ± 0.11, and 0.53 ± 0.19 L/hr/kg, respectively) (p = 0.037). Tirilazad clearance was weakly correlated with midazolam clearance (r2 = 0.129, p = 0.02). Tirilazad clearance is faster in premenopausal women than in postmenopausal women, but the effect of menopause on clearance is not reversed by hormone replacement. Tirilazad clearance in these women is weakly related to midazolam clearance, a marker of CYP3A activity.

Systemic Absorption of Clindamycin after Intravaginal Administration of Clindamycin Phosphate Ovule or Cream

The absolute bioavailability of clindamycin phosphate vaginal ovule with comparison to a reference treatment of clindamycin phosphate sterile solution, as well as the relative bioavailability of the ovule compared to clindamycin phosphate vaginal cream, was evaluated in 12 healthy adult female volunteers. Subjects were randomly assigned to receive either the ovule or cream formulation intravaginally for 3 consecutive days during the two‐way crossover portion of the study. During a third treatment period, all subjects received 100 mg of clindamycin as a 4‐minute intravenous infusion of clindamycin phosphate sterile solution (10 mg/mL). Clindamycin concentrations in serum were assayed by a high‐performance liquid chromatography method with detection by mass spectrometry. Pharmacokinetic analyses of the serum data indicated low systemic absorption of clindamycin from the vaginal cream (about 4%), consistent with results of previous bioavailability studies. Following intravaginal administration of the clindamycin phosphate ovule, systemic absorption averaged 30%, which was approximately sevenfold greater than after dosing with the vaginal cream. The higher drug absorption for the ovule may be related to differences in formulation effects on the vaginal membrane. Nevertheless, systemic exposure to clindamycin from the ovule is still considerably lower than from a therapeutic oral dose.

Gastro-Intestinal Regional Absorption Study of PNU-96391A in Healthy Volunteers

Clinical Pharmacology & Therapeutics (2003) 73, P50–P50; doi: