Study to Evaluate the PK of IV and PO Omadacycline in Children and Adolescents With Suspected or Confirmed Bacterial Infections

• Omadacycline Injection [Nuzyra] (Drug), also known as NUZYRA: Single dose of 100 mg omadacycline IV in 100 mL of normal saline
• Omadacycline Oral Tablet (Drug), also known as NUZYRA: Single dose of 300 mg omadacycline PO (2 x 150 mg tablets)

Primary outcomes

• Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 48hours (AUC0-48) of Omadacycline After IV Infusion [Predose (At least 15 minutes prior to IV infusion), 10 minutes, 0.5, 1, 2, 8, 24 and 48 hours after the end of IV infusion]: Blood samples were collected and analyzed to determine the AUC(0-48). Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• AUC(0-48) of Omadacycline After Oral Administration [Predose (At least 15 minutes prior to oral administration), 1, 2, 3, 8, 24 and 48 hours after dosing]: Blood samples were collected and analyzed to determine the AUC0-48. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• AUC From Time 0 to the Last Quantifiable Concentration (AUClast) of Omadacycline After IV Infusion [Pre-dose (At least 15 minutes prior to IV infusion), and 0.5, 1, 2, 8, 24 and 48 hours after the end of IV infusion]: Blood samples were collected and analyzed to determine the AUClast. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• AUClast of Omadacycline After Oral Administration [Predose (At least 15 minutes prior to oral administration), 1, 2, 3, 8, 24 and 48 hours after dosing]: Blood samples were collected and analyzed to determine the AUClast. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• AUC From Time 0 Extrapolated to Infinity (AUC0-inf) of Omadacycline After IV Infusion [Predose (At least 15 minutes prior to IV infusion), 10 minutes, 0.5, 1, 2, 8, 24 and 48 hours after the end of IV infusion]: Blood samples were collected and analyzed to determine AUC0-inf. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• AUC0-inf of Omadacycline After Oral Administration [Predose (At least 15 minutes prior to oral administration), 1, 2, 3, 8, 24 and 48 hours after dosing]: Blood samples were collected and analyzed to determine AUC0-inf. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• Maximum Observed Plasma Concentration (Cmax) of Omadacycline After IV Infusion [Predose (At least 15 minutes prior to IV infusion), 10 minutes, 0.5, 1, 2, 8, 24 and 48 hours after the end of IV infusion]: Blood samples were collected and analyzed to determine Cmax. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• Cmax of Omadacycline After Oral Administration [Predose (At least 15 minutes prior to oral administration), 1, 2, 3, 8, 24 and 48 hours after dosing]: Blood samples were collected and analyzed to determine Cmax. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• Time to Reach Maximum Observed Plasma Concentration (Tmax) of Omadacycline After IV Infusion [Predose (At least 15 minutes prior to IV infusion), 10 minutes, 0.5, 1, 2, 8, 24 and 48 hours after the end of IV infusion]: Blood samples were collected and analyzed to determine Tmax. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• Tmax of Omadacycline After Oral Administration [Predose (At least 15 minutes prior to oral administration), 1, 2, 3, 8, 24 and 48 hours after dosing]: Blood samples were collected and analyzed to determine Tmax. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• Elimination Half-life Associated With the Terminal Slope of the Semilogarithmic Concentration-time Curve (t1/2) of Omadacycline After IV Infusion [Predose (At least 15 minutes prior to IV infusion), 10 minutes, 0.5, 1, 2, 8, 24 and 48 hours after the end of IV infusion]: Blood samples were collected and analyzed to determine t1/2 and was calculated by using formula. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• t1/2 of Omadacycline After Oral Administration [Predose (At least 15 minutes prior to oral administration), 1, 2, 3, 8, 24 and 48 hours after dosing]: Blood samples were collected and analyzed to determine t1/2. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• Apparent Volume of Distribution During the Terminal Phase (Vz) of Omadacycline After IV Infusion [Predose (At least 15 minutes prior to IV infusion), 10 minutes, 0.5, 1, 2, 8, 24 and 48 hours after the end of IV infusion]: Blood samples were collected and analyzed to determine Vz. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.
• Systemic Clearance (CL) of Omadacycline After IV Infusion [Predose (At least 15 minutes prior to IV infusion), 10 minutes, 0.5, 1, 2, 8, 24 and 48 hours after the end of IV infusion]: Blood samples were collected and analyzed to determine CL. Pharmacokinetic parameters were estimated using non-compartmental methods and actual time data.

Secondary outcomes

• Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs), by Relationship to the Study Drug. [Up to Day 7]: An adverse event (AE) was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE was any event that had not been present before exposure to the study drug, or any event that had already been present but worsened in intensity or frequency after exposure.
• Number of Participants Reporting TEAE by Severity [Up to Day 7]: An adverse event (AE) was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE was any event that had not been present before exposure to the study drug, or any event that had already been present but worsened in intensity or frequency after exposure.
• Number of Participants Reporting TEAE, Serious Adverse Events (SAEs) and AE Leading to Discontinuation of Study Drug [Up to Day 7]: An AE was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE was any event that had not been present before exposure to the study drug, or any event that had already been present but worsened in intensity or frequency after exposure. An SAE was any adverse event that resulted in death, required hospitalization, persistent or significant disability, congenital anomaly.
• Number of Participants With Change From Baseline in Hematology Parameters [Up to Day 2]: Blood samples were collected for the assessment of complete blood count (CBC) including hemoglobin, hematocrit, leukocytes, platelets, mean cell volume, platelet count, white blood cell counts, and differential to include the absolute counts for neutrophils, lymphocytes, eosinophils, monocytes and basophils.
• Number of Participants With Change From Baseline in Serum Chemistry Parameters [Up to Day 2]: Blood samples were collected for the assessment of blood glucose, urea, creatinine, sodium, potassium, chloride, bicarbonate, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), total bilirubin, total protein, albumin, creatine phosphokinase (CK), calcium, phosphate, cholesterol, urate, amylase, lipase and gamma-glutamyl transpeptidase (GGT).
• Number of Participants With Change From Baseline in Vital Signs [Up to Day 2]: Vital signs included blood pressure, heart rate, and oral body temperature and were collected at the specified timepoints. Vital signs were measured after participants had remained in a supine position for at least 5 minutes using an automated calibrated device.
• Number of Participants With Clinically Significant Changes in Physical Examination [Up to Day 2]: A comprehensive physical examination was conducted, encompassing general appearance, skin, neck, eyes, ears, nose, throat, lungs, heart, abdomen, lymph nodes, extremities, and brief neurological exam.

Sex: All, ages: 8 Years to 17 Years

Inclusion Criteria:

* Male or female subjects, age 8 to < 18 (inclusive) who have written and signed parental/legal authorized representative (LAR) informed consent and pediatric assent.
* Currently hospitalized with a suspected or confirmed bacterial infection and receiving or planned to receive systemic antibiotic therapy other than omadacycline.
* Weight within the 5th and 95th percentile for age and sex.
* Subjects must not be pregnant or nursing at the time of enrollment, and must agree to use a highly effective birth control method during the study

Exclusion Criteria:

* Evidence of a medical condition that may pose a safety risk or impair study participation.
* Confirmed or suspected SARS-CoV-2 infection.
* Has a history of hypersensitivity or allergic reaction to any tetracycline antibiotic.
* Has received an investigational drug within the past 30 days.

Participant flow

Outcome results

• Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to 48hours (AUC0-48) of Omadacycline After IV Infusion (Primary), Geometric mean, hours*nanograms per milliliter (h*ng/ml): Adolescents, Cohort 1: 100 mg IV Omadacycline 8990 +/- 27.3; Children, Cohort 2: 100 mg IV Omadacycline 13300 +/- 40.1
• AUC(0-48) of Omadacycline After Oral Administration (Primary), Geometric mean, h*ng/ml: Adolescents, Cohort 1: 300 mg Oral Omadacycline 6860 +/- 81.5; Children, Cohort 2: 300 mg Oral Omadacycline 17900 +/- NA
• AUC From Time 0 to the Last Quantifiable Concentration (AUClast) of Omadacycline After IV Infusion (Primary), Geometric mean, h*ng/ml: Adolescents, Cohort 1: 100 mg IV Omadacycline 9010 +/- 27.4; Children, Cohort 2: 100 mg IV Omadacycline 13300 +/- 40.2
• AUClast of Omadacycline After Oral Administration (Primary), Geometric mean, h*ng/ml: Adolescents, Cohort 1: 300 mg Oral Omadacycline 6550 +/- 91.6; Children, Cohort 2: 300 mg Oral Omadacycline 9860 +/- 84.9
• AUC From Time 0 Extrapolated to Infinity (AUC0-inf) of Omadacycline After IV Infusion (Primary), Geometric mean, h*ng/ml: Adolescents, Cohort 1: 100 mg IV Omadacycline 9720 +/- 28.1; Children, Cohort 2: 100 mg IV Omadacycline 14100 +/- 38.5
• AUC0-inf of Omadacycline After Oral Administration (Primary), Geometric mean, h*ng/ml: Adolescents, Cohort 1: 300 mg Oral Omadacycline 7450 +/- 86.9; Children, Cohort 2: 300 mg Oral Omadacycline 18600 +/- NA
• Maximum Observed Plasma Concentration (Cmax) of Omadacycline After IV Infusion (Primary), Geometric mean, nanograms/milliliter (ng/ml): Adolescents, Cohort 1: 100 mg IV Omadacycline 1270 +/- 29.1; Children, Cohort 2: 100 mg IV Omadacycline 1600 +/- 51.6
• Cmax of Omadacycline After Oral Administration (Primary), Geometric mean, ng/ml: Adolescents, Cohort 1: 300 mg Oral Omadacycline 528 +/- 69.4; Children, Cohort 2: 300 mg Oral Omadacycline 946 +/- 42.7
• Time to Reach Maximum Observed Plasma Concentration (Tmax) of Omadacycline After IV Infusion (Primary), Median, hours: Adolescents, Cohort 1: 100 mg IV Omadacycline 0.66 (0.58 to 0.73); Children, Cohort 2: 100 mg IV Omadacycline 0.81 (0.73 to 1.08)
• Tmax of Omadacycline After Oral Administration (Primary), Median, hours: Adolescents, Cohort 1: 300 mg Oral Omadacycline 2.98 (2.00 to 3.13); Children, Cohort 2: 300 mg Oral Omadacycline 2.00 (1.03 to 3.00)
• Elimination Half-life Associated With the Terminal Slope of the Semilogarithmic Concentration-time Curve (t1/2) of Omadacycline After IV Infusion (Primary), Geometric mean, hours: Adolescents, Cohort 1: 100 mg IV Omadacycline 12.9 +/- 13.5; Children, Cohort 2: 100 mg IV Omadacycline 11.9 +/- 11.8
• t1/2 of Omadacycline After Oral Administration (Primary), Geometric mean, hours: Adolescents, Cohort 1: 300 mg Oral Omadacycline 12.7 +/- 31.2; Children, Cohort 2: 300 mg Oral Omadacycline 10.7 +/- NA
• Apparent Volume of Distribution During the Terminal Phase (Vz) of Omadacycline After IV Infusion (Primary), Geometric mean, liters: Adolescents, Cohort 1: 100 mg IV Omadacycline 191 +/- 27.7; Children, Cohort 2: 100 mg IV Omadacycline 122 +/- 48.0
• Systemic Clearance (CL) of Omadacycline After IV Infusion (Primary), Geometric mean, Liters per hour (L/h): Adolescents, Cohort 1: 100 mg IV Omadacycline 10.3 +/- 28.1; Children, Cohort 2: 100 mg IV Omadacycline 7.10 +/- 38.5
• Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs), by Relationship to the Study Drug. (Secondary), Count of participants, Participants: Adolescents, Cohort 1: 100 mg IV Omadacycline 0; Adolescents, Cohort 1: 300 mg Oral Omadacycline 2; Children, Cohort 2: 100 mg IV Omadacycline 1; Children, Cohort 2: 300 mg Oral Omadacycline 1
• Number of Participants Reporting TEAE by Severity (Secondary), Count of participants, Participants: Adolescents, Cohort 1: 100 mg IV Omadacycline 2; Adolescents, Cohort 1: 300 mg Oral Omadacycline 4; Children, Cohort 2: 100 mg IV Omadacycline 4; Children, Cohort 2: 300 mg Oral Omadacycline 0
• Number of Participants Reporting TEAE, Serious Adverse Events (SAEs) and AE Leading to Discontinuation of Study Drug (Secondary), Number, participants: Adolescents, Cohort 1: 100 mg IV Omadacycline 3; Adolescents, Cohort 1: 300 mg Oral Omadacycline 4; Children, Cohort 2: 100 mg IV Omadacycline 4; Children, Cohort 2: 300 mg Oral Omadacycline 3
• Number of Participants With Change From Baseline in Hematology Parameters (Secondary), Count of participants, Participants: Adolescents, Cohort 1: 100 mg IV Omadacycline 2; Adolescents, Cohort 1: 300 mg Oral Omadacycline 0; Children, Cohort 2: 100 mg IV Omadacycline 0; Children, Cohort 2: 300 mg Oral Omadacycline 0
• Number of Participants With Change From Baseline in Serum Chemistry Parameters (Secondary), Count of participants, Participants: Adolescents, Cohort 1: 100 mg IV Omadacycline 1; Adolescents, Cohort 1: 300 mg Oral Omadacycline 0; Children, Cohort 2: 100 mg IV Omadacycline 0; Children, Cohort 2: 300 mg Oral Omadacycline 0
• Number of Participants With Change From Baseline in Vital Signs (Secondary), Count of participants, Participants: Adolescents, Cohort 1: 100 mg IV Omadacycline 1; Adolescents, Cohort 1: 300 mg Oral Omadacycline 0; Children, Cohort 2: 100 mg IV Omadacycline 0; Children, Cohort 2: 300 mg Oral Omadacycline 0
• 1 more outcome measures not shown.

Adverse events

Time frame: Up to Day 7

Other adverse events by term

• Study Protocol (PDF, 2023-09-14)
• Statistical Analysis Plan (PDF, 2023-01-09)

• Amy Manley, Study director, Paratek Pharmaceuticals Inc