Pharmacokinetics of Single-Dose Intramuscular and Subcutaneous Injections of Buprenorphine in Common Marmosets (Callithrix jacchus)

Although buprenorphine is the most frequently used opioid analgesic in common marmosets (Callithrix jacchus), thereis limited information in the literature supporting current dosing regimens used for this species. The purpose of this study was to determine the pharmacokinetic profiles of single-dose buprenorphine HCl administered intramuscularly (IM) at 0.01 mg/kg in 6 adult marmosets (1.8 to 12.8 y old; 2 males, 4 females) and subcutaneously (SQ) at 0.01 mg/kg in 6 adult marmosets(2.3-4.4 y old; 3 males, 3 females) by mass spectrometry. Blood was collected at multiple time points from 0.25 to 24 h from unsedated animals following a hybrid sparse-serial sampling design. The maximal observed plasma concentration of buprenorphine (Cmax) administered IM (2.57 ± 0.95 ng/mL) was significantly higher than administered SQ (1.47 ± 0.61 ng/mL). However, the time to Cmax (Tmax) was not statistically different between routes (17.4 ± 6 min for IM and 19.8 ±7.8 min for SQ). The time of the last quantifiable concentration of buprenorphine was 5 ± 1.67 h for IM compared with 6.33 ± 1.51 h for SQ, which was not statistically different. The mean buprenorphine plasma concentration-time curves were used to propose a dosing frequency of 4 to 6 h for buprenorphine at 0.01 mg/kg IM or SQ based on a theoretical therapeutic plasma concentration threshold of 0.1 ng/mL. Based on the mean pharmacokinetic parameters and plasma-concentration time curves, both IM and SQ routes of buprenorphine at this dose provide a rapid increase in the plasma concentration of buprenorphine above the therapeutic threshold, and may be more effective for acute rather than long-lasting analgesia. Further studies are neededto examine repeated dosing regimens and the efficacy of buprenorphine in common marmosets.

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Variable Absorption of Clavulanic Acid After an Oral Dose of 25 mg/kg of Clavubactin® and Synulox® in Healthy Cats

The Scientific World JOURNAL ◽

10.1100/tsw.2002.287 ◽

2002 ◽

Vol 2 ◽

pp. 1369-1378 ◽

Cited By ~ 8

Author(s):

Tom B. Vree ◽

Eric Dammers ◽

Eri van Duuren

Keyword(s):

Single Dose ◽

Plasma Concentration ◽

Oral Dose ◽

Clavulanic Acid ◽

Phase I Study ◽

Pharmacokinetic Parameters ◽

High Efficacy ◽

Dose Ratio ◽

Concentration Time ◽

Crossover Phase

The aims of this investigation were to calculate the pharmacokinetic parameters and to identify parameters, based on individual plasma concentration-time curves of amoxicillin and clavulanic acid in cats, that may govern the observed differences in absorption of both drugs. The evaluation was based on the data from plasma concentration-time curves obtained following a single-dose, open, randomised, two-way crossover phase-I study, each involving 24 female cats treated with two Amoxi-Clav formulations (formulation A was Clavubactin® and formulation was B Synulox® ; 80/20 mg, 24 animals, 48 drug administrations). Plasma amoxicillin and clavulanic acid concentrations were determined using validated bioassay methods. The half-life of elimination of amoxicillin is 1.2 h (t1/2= 1.24 ± 0.28 h, Cmax= 12.8 ± 2.12 μg/ml), and that of clavulanic acid 0.6 h (t1/2= 0.63 ± 0.16 h, Cmax= 4.60 ± 1.68 μg/ml). There is a ninefold variation in the AUCtof clavulanic acid for both formulations, while the AUCtof amoxicillin varies by a factor of two. The highest clavulanic acid AUCtvalues indicate the best absorption; all other data indicate less absorption. Taking into account that the amoxicillin–to–clavulanic acid dose ratio in the two products tested was 4:1, the blood concentration ratios may actually vary much more, apparently without compromising the products’ high efficacy against susceptible microorganisms.

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Pharmacokinetics of Buprenorphine and Sustained-release Buprenorphine in Common Marmosets (Callithrix jacchus)

Journal of the American Association for Laboratory Animal Science ◽

10.30802/aalas-jaalas-20-000082 ◽

2020 ◽

Author(s):

Casey B Fitz ◽

Anna E Goodroe ◽

David E Moody ◽

Wenfang B Fang ◽

Saverio V Capuano III

Keyword(s):

Adverse Effects ◽

Sustained Release ◽

Peak Plasma ◽

Plasma Concentrations ◽

Callithrix Jacchus ◽

Terminal Phase ◽

Pharmacokinetic Parameters ◽

Common Marmosets ◽

Adult Age ◽

Concentration Time

Buprenorphine is an essential component of analgesic protocols in common marmosets (Callithrix jacchus). The use of buprenorphine HCl (BUP) and sustained-release buprenorphine (BSR) formulations has become commonplace in this species, but the pharmacokinetics have not been evaluated. Healthy adult (age, 2.4 to 6.8 y; 6 female and 6 male) common marmosets were enrolled in this study to determine the pharmacokinetic parameters, plasma concentration–time curves, and any apparent adverse effects of these compounds. Equal numbers of each sex were randomly assigned to receive BUP (0.02 mg/kg IM) orBSR (0.2 mg/kg SC), resulting in peak plasma concentrations (mean ± 1 SD) of 15.2 ± 8.1 and 2.8 ± 1.2 ng/mL, terminal phase t1/2 of 2.2 ± 1.0 and 32.6 ± 9.6 h, and AUC0-last of 16.1 ± 3.7 and 98.6 ± 42.7 ng×h/mL. The plasma concentrations of buprenorphine exceeded the proposed minimal therapeutic threshold (0.1 ng/mL) at 5 and 15 min after BUP and BSR administration,showing that both compounds are rapid-acting, and remained above that threshold through the final time points of 8 and 72h. Extrapolation of the terminal elimination phase of the mean concentration–time curves was used to develop the clinical dosing frequencies of 6 to 8 h for BUP and 3.0 to 3.5 d for BSR. Some adverse effects were observed after the administration of BUP to common marmosets in this study, thus mandating judicious use in clinical practice. BSR provided a safe, long-acting option for analgesia and therefore can be used to refine analgesic protocols in this species.

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Single-Dose Pharmacokinetics of a Pleconaril (VP63843) Oral Solution in Children and Adolescents

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.3.634 ◽

1999 ◽

Vol 43 (3) ◽

pp. 634-638 ◽

Cited By ~ 27

Author(s):

Gregory L. Kearns ◽

Susan M. Abdel-Rahman ◽

Laura P. James ◽

Douglas L. Blowey ◽

James D. Marshall ◽

...

Keyword(s):

Single Dose ◽

Oral Dose ◽

Rate Constant ◽

Pediatric Patients ◽

Elimination Rate ◽

Pharmacokinetic Parameters ◽

Parameter Estimates ◽

Time Data ◽

Concentration Time ◽

The Mean

ABSTRACT Pleconaril is an orally active, broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. In view of the potential pediatric use of pleconaril, we conducted a single-dose, open-label study to characterize the pharmacokinetics of this antiviral agent in pediatric patients. Following an 8- to 10-h period of fasting, 18 children ranging in age from 2 to 12 years (7.5 ± 3.1 years) received a single 5-mg/kg of body weight oral dose of pleconaril solution administered with a breakfast of age-appropriate composition. Repeated blood samples (n = 10) were obtained over 24 h postdose, and pleconaril was quantified from plasma by gas chromatography. Plasma drug concentration-time data for each subject were fitted to the curve by using a nonlinear, weighted (weight = 1/Y calc) least-squares algorithm, and model-dependent pharmacokinetic parameters were determined from the polyexponential parameter estimates. Pleconaril was well tolerated by all subjects. A one-compartment open-model with first-order absorption best described the plasma pleconaril concentration-time profile in 13 of the subjects over a 24-h postdose period. Pleconaril pharmacokinetic parameters (means ± standard deviations) for these 13 patients were as follows. The maximum concentration of the drug in serum (C max) was 1,272.5 ± 622.1 ng/ml. The time to C max was 4.1 ± 1.5 h, and the lag time was 0.75 ± 0.56 h. The apparent absorption rate constant was 0.75 ± 0.48 1/h, and the elimination rate constant was 0.16 ± 0.07 1/h. The area under the concentration-time curve from 0 to 24 h was 8,131.15 ± 3,411.82 ng · h/ml. The apparent total plasma clearance was 0.81 ± 0.86 liters/h/kg, and the apparent steady-state volume of distribution was 4.68 ± 2.02 liters/kg. The mean elimination half-life of pleconaril was 5.7 h. The mean plasma pleconaril concentrations at both 12 h (250.4 ± 148.2 ng/ml) and 24 h (137.9 ± 92.2 ng/ml) after the single 5-mg/kg oral dose in children were higher than that from in vitro studies reported to inhibit >90% of nonpolio enterovirus serotypes (i.e., 70 ng/ml). Thus, our data support the evaluation of a 5-mg/kg twice-daily oral dose of pleconaril for therapeutic trials in pediatric patients with enteroviral infections.

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Oral bioavailability and pharmacokinetics of ciprofloxacin in patients with AIDS.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.7.1508 ◽

1997 ◽

Vol 41 (7) ◽

pp. 1508-1511 ◽

Cited By ~ 10

Author(s):

R C Owens ◽

K B Patel ◽

M A Banevicius ◽

R Quintiliani ◽

C H Nightingale ◽

...

Keyword(s):

Absolute Bioavailability ◽

Pharmacokinetic Parameters ◽

Crossover Fashion ◽

Time Curve ◽

Mean Values ◽

Severe Diarrhea ◽

Concentration Time ◽

Infectious Gastroenteritis ◽

Dosing Regimens ◽

The Mean

Few reports on the effects of AIDS on the absorption of orally (p.o.) administered agents exist. To help fill this informational gap, we administered ciprofloxacin to 12 patients with AIDS by two dosing regimens (400 mg given intravenously [i.v.] and 500 mg given p.o. every 12 h) in a randomized, crossover fashion. Pharmacokinetic parameters were determined by noncompartmental methods. Mean values (+/- standard deviations [SD]) for p.o. ciprofloxacin were as follows: peak concentration of drug in serum (Cmax), 2.94 +/- 0.51 microg/ml; time to Cmax, 1.38 +/- 0.43 h; area under the concentration-time curve from 0 to 12 h (AUC(0-12)), 12.13 +/- 3.21 microg x h/ml; and half-life (t(1/2)), 3.86 +/- 0.48 h. Mean values (+/- SD) for i.v. ciprofloxacin were as follows: Cmax, 3.61 +/- 0.82 microg/ml; time to Cmax, 1.0 h; AUC(0-12), 11.92 +/- 2.92 microg x h/ml; and t(1/2), 3.98 +/- 0.94 h. The mean percent absolute bioavailability for ciprofloxacin was calculated to be 82% +/- 13%, similar to the value for healthy volunteers. We conclude that ciprofloxacin when administered p.o. to patients with AIDS is well absorbed, as evidenced by excellent bioavailability and is not affected by gastrointestinal changes in the absence of infectious gastroenteritis and severe diarrhea.

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Pharmacokinetics and Bioequivalence Study of Two Ciprofloxacin Hydrochloride Tablets in Chinese Healthy Volunteers Under Fasting and Fed Conditions: A Randomized, Open-Label, Two-Formulation, Two-Sequence, Two-Period, Single-Dose Crossover Study.

10.21203/rs.3.rs-103736/v1 ◽

2020 ◽

Author(s):

Fei Qin ◽

Gan-Mi Wang ◽

Jin-Ying Huang ◽

Jia-Rong Wu ◽

Wen-Jie Song ◽

...

Keyword(s):

Single Dose ◽

Plasma Concentration ◽

Oral Dose ◽

Single Oral Dose ◽

Pharmacokinetic Parameters ◽

Open Label ◽

Time Curve ◽

Ciprofloxacin Hydrochloride ◽

Concentration Time ◽

Plasma Concentration Time Curve

Abstract BackgroundCiprofloxacin is a broad-spectrum fluoroquinolone antibiotic which is active against a wide range of Gram-positive and Gram-negative bacteria. The study mainly aimed to determine the bioequivalence of two branded ciprofloxacin hydrochloride tablets (250 mg) under the fasting and fed conditions.MethodsThe study was carried out in 48 healthy Chinese subjects under fasting and fed conditions with a randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover design. In each period of the study, the subjects were assigned to receive a single oral dose of 250 mg of ciprofloxacin hydrochloride. Blood samples were collected from an hour before dosing to 36 h after administration with 16 time points in total. The bioequivalence analysis was performed after ln-transformation of the ciprofloxacin pharmacokinetic parameters including maximum concentration (Cmax), area under the plasma concentration–time curve from time 0 to time t (AUC0-t), area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞). Two formulations are considered bioequivalent if the 90% confidence intervals (CIs) for the test/reference geometric mean ratios (GMRs) for the ln-transformed pharmacokinetic parameters fall within the standard acceptance range of 80% – 125%. ResultsIn total of 48 subjects were enrolled in the fasting and fed studies, and one of the subjects was excluded before the administration. In the fasting study, the 90% CIs for the test/reference GMRs of the ln-transformed data for Cmax, AUC0–t, and AUC0–∞ were 85.41% to 100.97%, 95.40% to 100.27%, and 95.48% to 100.30%, respectively. For the fed study, the 90% CIs for the test/reference GMRs of the ln-transformed data for Cmax, AUC0–t, and AUC0–∞ were 90.15% to 113.75%, 99.10% to 103.77% and 99.11% to 103.80%, respectively. A total of 8 of 47 subjects experienced AEs in the fasting and fed studies.ConclusionsIn the study, the generic (test) product of ciprofloxacin hydrochloride 250 mg was bioequivalent to the innovator (reference) product after a single oral dose administration under the fasting and fed conditions. Both two brands of ciprofloxacin tablets were safe and well tolerated.Trial registrationThe clinical trial was registered at Center for the Drug Evaluation of the National Medical Products Administration (registration number: CTR20171152; date of registration：September 25, 2017; http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml).

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Lack of Effect of Ginkgo biloba on Voriconazole Pharmacokinetics in Chinese Volunteers Identified as CYP2C19 Poor and Extensive Metabolizers

Annals of Pharmacotherapy ◽

10.1345/aph.1l537 ◽

2009 ◽

Vol 43 (4) ◽

pp. 726-731 ◽

Cited By ~ 28

Author(s):

He-Ping Lei ◽

Guo Wang ◽

Lian-Sheng Wang ◽

Dong-sheng Ou-yang ◽

Hao Chen ◽

...

Keyword(s):

Single Dose ◽

Ginkgo Biloba ◽

Poor Metabolizers ◽

Pharmacokinetic Parameters ◽

Extensive Metabolizers ◽

Herbal Supplements ◽

Time Curve ◽

Concentration Time ◽

Apparent Clearance ◽

Randomized Crossover Study

Background: Ginkgo biloba is one of the most popular herbal supplements in the world. The supplement has been shown to induce the enzymatic activity of CYP2C19, the main cytochrome P450 isozyme involved in voriconazole metabolism. Because this enzyme exhibits genetic polymorphism, the inductive effect was expected to be modulated by the CYP2C19 metabolizer status. Objective: To examine the possible effects of Ginkgo biloba as an inducer of CYP2C19 on single-dose pharmacokinetics of voriconazole in Chinese volunteers genotyped as either CVP2C19 extensive or poor metabolizers. Methods: Fourteen healthy, nonsmoking volunteers–7 CYP2C19 extensive metabolizers (2C19*1/2C19*1) and 7 poor metabolizers (2C19*2/2C19*2)–were selected to participate in this study. Pharmacokinetics of oral voriconazole 200 mg after administration of Ginkgo biloba 120 mg twice daily for 12 days were determined for up to 24 hours by liquid chromatography–electrospray tandem mass spectrometry in a 2-phase randomized crossover study with 4-week washout between phases. Results: For extensive metabolizers, the median value for voriconazole area under the plasma concentration–time curve from zero to infinity (AUC0-00) was 5.17 μg•h/mL after administration of voriconazole alone and 4.28 μg•/mL after voriconazole with Ginkgo biloba (p > 0.05). The other pharmacokinetic parameters of voriconazole such as AUC0-24, time to reach maximum concentration, half-life, and apparent clearance also did not change significantly for extensive metabolizers in the presence of Ginkgo biloba. Pharmacokinetic parameters followed a similar pattern for poor metabolizers. Conclusions: The results suggest that 12 days of treatment with Ginkgo biloba did not significantly alter the single-dose pharmacokinetics of voriconazole in either CYP2C19 extensive or poor metabolizers. Therefore, the pharmacokinetic interactions between voriconazole and Ginkgo biloba may have limited clinical significance.

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Safety, toleration, and pharmacokinetics of intravenous azithromycin.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.11.2577 ◽

1996 ◽

Vol 40 (11) ◽

pp. 2577-2581 ◽

Cited By ~ 48

Author(s):

D R Luke ◽

G Foulds ◽

S F Cohen ◽

B Levy

Keyword(s):

Half Life ◽

Active Drug ◽

Slow Release ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Concentration Time ◽

Elimination Half ◽

The Mean ◽

Male Subjects

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 micrograms/ml after a 4-g dose) and the area under the concentration-time curve (82 micrograms.h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.

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Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Hepatic Impairment

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.50.5.1721-1726.2006 ◽

2006 ◽

Vol 50 (5) ◽

pp. 1721-1726 ◽

Cited By ~ 23

Author(s):

Xiao-Jian Zhou ◽

Thomas C. Marbury ◽

Harry W. Alcorn ◽

William B. Smith ◽

Gloria Dubuc Patrick ◽

...

Keyword(s):

Hepatitis B Virus ◽

Plasma Concentration ◽

Hepatitis B ◽

Hepatic Impairment ◽

Hepatic Function ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Concentration Time ◽

Chronic Hepatitis B Virus ◽

B Virus

ABSTRACT This study evaluated the effect of hepatic impairment on the pharmacokinetics of telbivudine, an investigational nucleoside antiviral for the treatment of chronic hepatitis B virus infection. Twenty-four subjects were assigned to four hepatic function groups (normal function and mild, moderate, and severe impairment, with six subjects in each group) on the basis of Child-Pugh scores. The subjects were administered a single oral dose of 600 mg telbivudine, and blood samples were collected over a 48-h interval for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. Telbivudine plasma concentration-time profiles were similar across the four hepatic function groups. The principal pharmacokinetic parameters of drug exposure, i.e., the maximum plasma concentration and area under the drug concentration-time curve, were comparable between subjects with various degrees of hepatic impairment and those with normal hepatic function. Results from this single-dose pharmacokinetic assessment therefore provide a pharmacologic rationale for further evaluation of the safety and efficacy of telbivudine in hepatitis B virus-infected patients with decompensated liver diseases.

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Pharmacokinetics of Telbivudine in Healthy Subjects and Absence of Drug Interaction with Lamivudine or Adefovir Dipivoxil

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01313-05 ◽

2006 ◽

Vol 50 (7) ◽

pp. 2309-2315 ◽

Cited By ~ 31

Author(s):

Xiao-Jian Zhou ◽

Barbara A. Fielman ◽

Deborah M. Lloyd ◽

George C. Chao ◽

Nathaniel A. Brown

Keyword(s):

Single Dose ◽

Steady State ◽

Plasma Concentration ◽

Healthy Subjects ◽

Adefovir Dipivoxil ◽

Geometric Mean ◽

Time Curve ◽

Concentration Time ◽

Plasma Pharmacokinetics ◽

Plasma Concentration Time Curve

ABSTRACT Two phase I studies were conducted to assess the plasma pharmacokinetics of telbivudine and potential drug-drug interactions between telbivudine (200 or 600 mg/day) and lamivudine (100 mg/day) or adefovir dipivoxil (10 mg/day) in healthy subjects. Study drugs were administered orally. The pharmacokinetics of telbivudine were characterized by rapid absorption with biphasic disposition. The maximum concentrations in plasma (C max) were reached at median times ranging from 2.5 to 3.0 h after dosing. Mean single-dose C max and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) were 1.1 and 2.9 μg/ml and 7.4 and 21.8 μg · h/ml for the 200- and 600-mg telbivudine doses, respectively. Steady state was reached after daily dosing for 5 to 7 days. The mean steady-state C max and area under the plasma concentration-time curve over the dosing interval (AUCτ) were 1.2 and 3.4 μg/ml and 8.9 and 27.5 μg · h/ml for the 200- and 600-mg telbivudine repeat doses, respectively. The steady-state AUCτ of telbivudine was 23 to 57% higher than the single-dose values. Concomitant lamivudine or adefovir dipivoxil did not appear to significantly alter the steady-state plasma pharmacokinetics of telbivudine; the geometric mean ratios and associated 90% confidence interval (CI) for the AUCτ of telbivudine alone versus in combination were 106.3% (92.0 to 122.8%) and 98.6% (86.4 to 112.5%) when coadministered with lamivudine and adefovir dipivoxil, respectively. Similarly, the steady-state plasma pharmacokinetics of lamivudine or adefovir were not markedly affected by the coadministration of telbivudine; the geometric mean ratios and associated 90% CI, alone versus in combination with telbivudine, were 99.0% (87.1 to 112.4%) and 92.2% (84.0 to 101.1%), respectively, for the lamivudine and adefovir AUCτ values. Moreover, the combination regimens studied were well tolerated in all subjects. The results from these studies provide pharmacologic support for combination therapy or therapy switching involving telbivudine, lamivudine, and adefovir dipivoxil for the treatment of chronic hepatitis B virus infection.

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1159. Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Pediatric Participants With Confirmed or Suspected Gram-negative Bacterial Infections: A Phase 1b, Open-label, Single-Dose Clinical Trial

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1352 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S671-S671

Author(s):

John S Bradley ◽

Nataliia Makieieva ◽

Camilla Tøndel ◽

Emmanuel Roilides ◽

Matthew S Kelly ◽

...

Keyword(s):

Single Dose ◽

Plasma Concentration ◽

Bacterial Infections ◽

Geometric Mean ◽

Complicated Urinary Tract Infection ◽

Research Support ◽

Open Label ◽

Gram Negative ◽

Age Cohorts ◽

The Mean

Abstract Background Imipenem/cilastatin/relebactam (IMI/REL) is approved for treating hospital-acquired/ventilator-associated bacterial pneumonia, complicated urinary tract infection, and complicated intra-abdominal infection in adults. This study assessed single-dose pharmacokinetics (PK), safety, and tolerability of IMI/REL in neonatal and pediatric participants with confirmed or suspected gram-negative bacterial infections. Methods This was a phase 1, open-label, non-comparative study (NCT03230916). Age- and weight-adjusted dosing is summarized in Table 1. The primary objective was to characterize the PK profiles for imipenem and relebactam after a single intravenous dose of IMI/REL. PK parameters were analyzed using population modeling. The PK target for imipenem was the percent time of the dosing interval that the unbound plasma concentration exceeded the minimum inhibitory concentration (%fT >MIC) of ≥30% (MIC used, 2 µg/mL). The PK target for relebactam was an area under the curve (AUC)/MIC ratio >8 (MIC used, 2 µg/mL), corresponding to AUC0-24h >58.88 μM∙h. Safety and tolerability were assessed for up to 14 days after drug infusion. Results Of the 46 participants who received IMI/REL, 42 were included in the PK analysis. The mean plasma concentration-time profiles for imipenem and relebactam were generally comparable across age cohorts (Figure). For imipenem, the geometric mean %ƒT >MIC ranged from 50% to 94% and the mean maximum concentration (Cmax) ranged from 65 μM to 126 μM (Table 2). For relebactam, the geometric Cmax ranged from 33 μM to 87 μM and mean AUC0-6h ranged from 51 μM·h to 159 μM·h across the age cohorts (Table 2). IMI/REL was well tolerated with 8 (17.4%) participants experiencing ≥1 adverse events (AE) and 2 (4.3%) participants experiencing AE that were deemed drug related by the investigator. Drug-related AE were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, and diarrhea, which were non-serious, mild in severity, and resolved within the follow-up period of 14 days. Figure 1 Conclusion Imipenem and relebactam exceeded the pediatric plasma PK targets across pediatric age cohorts in the study; the single doses of IMI/REL were well tolerated. These results will inform IMI/REL dose selection for further pediatric clinical evaluation. Disclosures Camilla Tøndel, MD, PhD, Merck & Co., Inc., (Grant/Research Support) Emmanuel Roilides, MD, PhD, FIDSA, FAAM, FESCMID, FECMM, FISAC, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Matthew S. Kelly, MD, MPH, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Munjal Patel, PhD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Pavan Vaddady, PhD, Merck Sharp & Dohme Corp. (Employee) Alok Maniar, MD, MPH, Merck Sharp & Dohme Corp. (Employee, Shareholder) Ying Zhang, PhD, Merck & Co., Inc. (Employee, Shareholder) Amanda Paschke, MD MSCE, Merck Sharp & Dohme Corp. (Employee, Shareholder) Joan R. Butterton, MD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck (Employee)

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