Trial Outcomes & Findings for Ketorolac in Postoperative Infants: Pharmacokinetics and Safety (NCT NCT01260883)

NCT ID: NCT01260883

Last Updated: 2013-06-13

Results Overview

stereo-isomer specific clearance determined by population-based pharmacokinetic analysis (NONMEM)

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 77 participants
• Primary outcome timeframe: 24 hours following surgery
• Results posted on: 2013-06-13

Participant Flow

Infants less than 18 months of age, having surgery requiring inpatient admission, from 2001 through 2008, with normal renal and liver function, not on chronic medication , not prematurely born, were selected.

If screening lab studies (blood urea nitrogen [BUN], creatinine, liver transaminase concentrations, urinalysis) were abnormal infants were excluded. If postoperative concerns precluded blood sampling or if sampling intravenous (iv) catheters did not function, infants were excluded.Of 77 infants screened, 51 infants started study

Participant milestones

Measure	Ketorolac 1 mg/kg Intravenous intravenous infusion over 10 minutes	Ketorolac 0.5 mg/kg Intravenous intravenous infusion over 10 minutes	Dextrose 5% in Water (D5W) intravenous infusion over 10 minutes
Overall Study STARTED	22	11	18
Overall Study COMPLETED	22	11	18
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Ketorolac in Postoperative Infants: Pharmacokinetics and Safety

Baseline characteristics by cohort

Measure	Ketorolac 1 mg/kg Intravenous n=22 Participants intravenous infusion over 10 minutes	Ketorolac 0.5 mg/kg Intravenous n=11 Participants intravenous infusion over 10 minutes	Dextrose 5% in Water (D5W) n=18 Participants intravenous infusion over 10 minutes	Total n=51 Participants Total of all reporting groups
Age, Categorical <=18 years	22 Participants n=5 Participants	11 Participants n=7 Participants	18 Participants n=5 Participants	51 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age Continuous	8.9 months STANDARD_DEVIATION 3.8 • n=5 Participants	9.4 months STANDARD_DEVIATION 4.2 • n=7 Participants	9 months STANDARD_DEVIATION 3.8 • n=5 Participants	9.1 months STANDARD_DEVIATION 3.9 • n=4 Participants
Sex: Female, Male Female	12 Participants n=5 Participants	6 Participants n=7 Participants	8 Participants n=5 Participants	26 Participants n=4 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants	25 Participants n=4 Participants
Region of Enrollment United States	22 participants n=5 Participants	11 participants n=7 Participants	18 participants n=5 Participants	51 participants n=4 Participants

PRIMARY outcome

Timeframe: 24 hours following surgery

Population: of 25 infants aged 2-6 months enrolled, 11 were excluded. 8 received drug, 6 received placebo; this is a subset of the 77 enrolled infants (aged 2-18 months) of whom 51 completed the study. Infants receiving drug at 0.5 or 1 mg/kg were reported together, since no difference in drug handling was seen.

stereo-isomer specific clearance determined by population-based pharmacokinetic analysis (NONMEM)

Outcome measures

Measure	S- Ketorolac Clearance n=8 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology	R+ Ketorolac Clearance n=8 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)	Placebo stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Clearance of S-ketorolac and R+ Ketorolac in 2-6 Month Old Infants Following Surgery	30.7 ml/min Standard Error 22.8	6.5 ml/min Standard Error 2.2	—

PRIMARY outcome

Timeframe: 24 hours after surgery

Population: infants enrolled but did not complete protocol if abnormal laboratory studies or intravenous catheters were not functioning prior to study drug infusion. Of 77 enrolled, 51 completed study; of the 33 given ketorolac,8 were aged 2-6 months. Doses of 0.5 or 1 mg/kg were handled similarly so reported together.

stereo-specific ketorolac analysis using population-based analysis (NONMEM)for ketorolac given intravenously 24 hours after surgery in 2-6 month old infants

Outcome measures

Measure	S- Ketorolac Clearance n=8 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology	R+ Ketorolac Clearance n=8 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)	Placebo stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Central Volume of Distribution for S- and R+ Ketorolac in 2-6 Month Old Infants	1480 ml Standard Error 920	992 ml Standard Error 440	—

PRIMARY outcome

Timeframe: 24 hours post surgery

Population: 25 infants aged 2-6 months enrolled; 11 excluded for no sampling intravenous access. 8 infants received drug, 6 received placebo. No difference in analysis of doses of 0.5 or 1 mg/kg so reported together.

peripheral volume of distribution for ketorolac stereo-isomers determined by population kinetic analysis (NONMEM)

Outcome measures

Measure	S- Ketorolac Clearance n=8 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology	R+ Ketorolac Clearance n=8 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)	Placebo stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Peripheral Volume of Distribution for S- and R+ Ketorolac in 2-6 Month Old Infants	341 ml Standard Deviation 342	658 ml Standard Deviation 207	—

PRIMARY outcome

Timeframe: 24 hours after surgery

Population: total infants enrolled was 77; 26 were excluded before study procedures began. Of 51 infants completing the study, 8 infants aged 2-6 months received drug.No difference in analysis at doses of 0.5 or 1 mg/kg so reported together.

half-life calculated from non-compartmental analysis of ketorolac isomers in 2-6 month old infants given intravenous ketorolac following surgery

Outcome measures

Measure	S- Ketorolac Clearance n=8 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology	R+ Ketorolac Clearance n=8 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)	Placebo stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Half-life of S- and R+ Ketorolac in 2-6 Month Old Infants	67 min Standard Error 33	197 min Standard Error 82	—

PRIMARY outcome

Timeframe: 24 hours after surgery

Population: 52 infants aged 6-18 months enrolled; 15 excluded for abnormal laboratory results or intravenous sampling catheters that did not allow sampling. 25 infants aged 6-18 months received ketorolac, 12 received placebo. Doses of 0.5 or 1 mg/kg reported together since no difference found in handling.

stereo-specific ketorolac clearance by population-based analysis (NONMEM)

Outcome measures

Measure	S- Ketorolac Clearance n=25 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology	R+ Ketorolac Clearance n=25 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)	Placebo stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Clearance of S- and R+ Ketorolac in 6-18 Month Old Infants	45.3 ml/min Standard Error 12.1	7.52 ml/min Standard Error 9.3	—

PRIMARY outcome

Timeframe: 24 hours after surgery

Population: of 52 enrolled infants aged 6-18 months, 37 completed the study. Of these, 25 received drug, 12 placebo.Doses of 0.5 or 1 mg/kg showed no difference in handling so reported together.

population-based kinetic analysis of ketorolac isomers following intravenous infusion in infants after surgery

Outcome measures

Measure	S- Ketorolac Clearance n=25 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology	R+ Ketorolac Clearance n=25 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)	Placebo stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Volume of Distribution for Ketorolac Isomers in 6-18 Month Old Infants	2320 ml Standard Error 14.6	1200 ml Standard Error 13.6	—

PRIMARY outcome

Timeframe: 24 hours after surgery

Population: 52 infants aged 6-18 months enrolled; 15 excluded. 25 received ketorolac, 12 received placebo. Drug handling not different at doses of 0.5 or 1 mg/kg so reported together.

population-based analysis of ketorolac stereo-isomers

Outcome measures

Measure	S- Ketorolac Clearance n=25 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology	R+ Ketorolac Clearance n=25 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)	Placebo stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Ketorolac Stereo-isomer Volume of Distribution Peripheral in 6-18 Month Old Infants	224 ml Standard Error 86	828 ml Standard Error 13	—

PRIMARY outcome

Timeframe: 24 hours after surgery

Population: 52 infants of the 77 total were aged 6-18 months. 15 were excluded for abnormal laboratory values at screening or for lack of access to draw blood samples. 25 received drug, 12 placebo.Doses 0.5 or 1 mg/kg reported together since no difference in analysis.

noncompartmental pharmacokinetic analysis of ketorolac stereo-isomers after intravenous infusion in postoperative infants

Outcome measures

Measure	S- Ketorolac Clearance n=25 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology	R+ Ketorolac Clearance n=25 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)	Placebo stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Half-life of Ketorolac Stereo-isomers in 6-18 Month Old Infants After Surgery	50.1 min Standard Deviation 42	238 min Standard Deviation 48	—

SECONDARY outcome

Timeframe: first day after surgery

Population: 25 infants enrolled but 11 excluded. 8 received ketorolac, 6 placebo. total morphine given over 12 hours following infusion collected

total morphine given intravenously in the 12 hours following receiving intravenous ketorolac or placebo

Outcome measures

Measure	S- Ketorolac Clearance n=8 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology	R+ Ketorolac Clearance n=6 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)	Placebo stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Morphine Use in 2-6 Month Old Infants Given Ketorolac or Placebo Following Surgery	0.12 mg/kg Standard Deviation 0.28	0.08 mg/kg Standard Deviation 0.12	—

SECONDARY outcome

Timeframe: 12 hours after ketorolac or placebo infusion

Population: 25 infants aged 2-6 months enrolled; 11 excluded. 8 received ketorolac, 6 placebo

continuous oximetry monitoring of room air saturation was collected for 12 hours after intravenous infusion of ketorolac or placebo

Outcome measures

Measure	S- Ketorolac Clearance n=8 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology	R+ Ketorolac Clearance n=6 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)	Placebo stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Percent Time With Room Air Oximetry Saturations Under 90% in 2-6 Month Infants	NA percentage of time in 12 h after drug Interval 2.1 to 7.3 Median not calculated due to small sample size	NA percentage of time in 12 h after drug Interval 1.9 to 5.1 Median not calculated due to small sample size	—

SECONDARY outcome

Timeframe: 24 hours after surgery

Population: 52 infants aged 6-18 months enrolled; 15 excluded. 25 received ketorolac and 12 received placebo infusion after surgery

total amount of morphine given for 12 hours after ketorolac or placebo infusion in 6-18 month old infants after surgery

Outcome measures

Measure	S- Ketorolac Clearance n=25 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology	R+ Ketorolac Clearance n=12 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)	Placebo stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Total Morphine Use in 6-18 Month Old Infants After Ketorolac or Placebo Intravenous Infusion After Surgery	1.8 mg/kg Standard Deviation 1.5	2.2 mg/kg Standard Deviation 1.4	—

SECONDARY outcome

Timeframe: 24 hours after surgery

Population: 52 infants aged 6-18 months enrolled; 15 excluded. 25 received ketorolac, 12 received placebo

continuous oximetry monitoring for 12 hours after ketorolac or placebo intravenous infusion in 6-18 month old infants after surgery

Outcome measures

Measure	S- Ketorolac Clearance n=25 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology	R+ Ketorolac Clearance n=12 Participants stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)	Placebo stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Oximetry Saturation Under 90% After Ketorolac or Placebo Infusion in 6-18 Month Old Infants	0.8 per cent time of 12 hours Standard Deviation 0.8	1 per cent time of 12 hours Standard Deviation 1	—

Adverse Events

Ketorolac 1 mg/kg Intravenous

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Ketorolac 0.5 mg/kg Intravenous

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Dextrose 5% in Water (D5W)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Anne Lynn MD

Seattle Children's Hospital

Phone: 206 987-2518

Email: anne.lynn@seattlechildrens.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place