A Study To Investigate The Pharmacokinetics, Safety And Tolerability Of An Intravenous And Oral Form Of A Compound In Subjects With Varying Degrees Of Renal Impairment And Normal Renal Function

Pneumonia Clinical Trial

Official title:

An Open-label, 2-way Crossover Study To Investigate The Pharmacokinetics, Safety And Tolerability Of Iv Cp-70429 And Oral Pf-03709270 In Subjects With Varying Degrees Of Renal Impairment And Normal Renal Function

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00759564
• Other study ID #: A8811009
• Secondary ID: 2009-017796-20
• Status: Completed
• Phase: Phase 1
• First received: September 23, 2008
• Last updated: February 10, 2016
• Start date: November 2008
• Est. completion date: March 2010

Study information

• Verified date: February 2016
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study will evaluate what effect renal dysfunction has on a drug that has an intravenous (CP-70,429) and an oral form (PF-03709270).

Description:

To evaluate the pharmacokinetics and safety.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: March 2010
• Est. primary completion date: March 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

Subjects must meet one of the following renal function categories:

• Normal renal function (CLcr >80 mL/min).

• Mild renal impairment (CLcr >50 and <80 mL/min).

• Moderate renal impairment (CLcr >30 and <50 mL/min).

• Severe renal impairment (CLcr <30 mL/min).

Exclusion Criteria:

Women who are pregnant or nursing or women who are of childbearing potential. History of clinically significant allergies, including seasonal allergies, and especially drug hypersensitivity including known allergies to components of the study drug formulation, penicillin, carbapenems and/or cephalosporin antibiotics (eg, amoxicillin, amoxicillin/clavulanate, ampicillin, cefadroxil, cephalexin, cefaclor and cefixime).

Subjects should not have evidence of a history of the following:

• normal renal function: clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological or allergic disease.

• renal impairment: any clinically significant (hepatic, cardiac or pulmonary or subjects with acute nephritic syndrome) diseases (except diabetes). Stable co-morbid disease where it is unlikely that the disease and medication will alter the outcome of the study will be allowed.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Pneumonia
• Renal Insufficiency

Intervention

Drug:
• CP-70,429 and PF-03709270
Study Periods 1 and 2 will be separated by a minimum of 14 days. In Period 1, subjects will receive a single dose of CP-70429 (800 mg given as a 1.5 hour intravenous infusion), while in Period 2, subjects will receive a single oral dose of PF-03709270 (1000 mg).

Locations

Country	Name	City	State
Belgium	Pfizer Clinical Research Unit	Bruxelles
United States	Centurion Clinical Research	Indianapolis	Indiana

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Observed Plasma Concentration (Cmax) of CP-70429 Following CP-70,429 Intravenous Dose	PF-03709270 is an oral prodrug of CP-70,429. Upon oral absorption, PF-03709270 is rapidly hydrolyzed, yielding the active drug CP-70,429. Cmax of CP-70429 following CP-70,429 intravenous dose was reported.	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Primary	Time to Reach Maximum Observed Plasma Concentration (Tmax) of CP-70429 Following CP-70,429 Intravenous Dose		0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Primary	Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of CP-70429 Following CP-70,429 Intravenous Dose	Area under the plasma concentration time-curve from zero (pre-dose) to the time of last measured concentration (AUClast).	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Primary	Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0-inf)] of CP-70,429 Following CP-70,429 Intravenous Dose	AUC (0-inf) is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf).	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Primary	Renal Clearance (CLr) of CP-70429 Following CP-70,429 Intravenous Dose	Renal clearance was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau).	0 (pre-dose), 0 to 6, 6 to 12, 12 to 24 hours post-dose	No
Primary	Maximum Observed Plasma Concentration (Cmax) of CP-70429 Following PF-03709270 Oral Dose	PF-03709270 is an oral prodrug of CP-70,429. Upon oral absorption, PF-03709270 is rapidly hydrolyzed, yielding the active drug CP-70,429. Cmax of CP-70429 following CP-70,429 intravenous dose was reported.	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Primary	Time to Reach Maximum Observed Plasma Concentration (Tmax) of CP-70429 Following PF-03709270 Oral Dose		0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Primary	Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of CP-70429 Following PF-03709270 Oral Dose	Area under the plasma concentration time-curve from zero (pre-dose) to the time of last measured concentration (AUClast).	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Primary	Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0-inf)] of CP-70429 Following PF-03709270 Oral Dose	AUC (0-inf) is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf).	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Primary	Renal Clearance (CLr) of CP-70429 Following PF-03709270 Oral Dose	Renal clearance was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau).	0 (pre-dose), 0 to 6, 6 to 12, 12 to 24 hours post-dose	No
Secondary	Terminal Elimination Half Life (t1/2) of CP-70429 Following CP-70,429 Intravenous Dose	Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half.	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Secondary	Terminal Elimination Half Life (t1/2) of CP-70429 Following PF-03709270 Oral Dose	Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half.	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Secondary	Clearance (CL)	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing given intravenous dose by AUC inf. AUC inf is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf).	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Secondary	Apparent Oral Clearance (CL/F)	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. It was calculated by dividing the given oral dose by AUCinf. AUC inf is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf).	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Secondary	Duration of Plasma Concentrations of CP-70429 Exceeding 0.5 Microgram Per Milliliter Following Intravenous Dose	Duration was calculated by subtracting the time at which the plasma concentrations exceeded 0.5 microgram per milliliter (mcg/mL) at the ascending part of the concentration-time profile from the time at which the plasma concentrations fell below 0.5 mcg/mL at the descending part of the profile. If these times fell between 2 observed concentrations, a method of linear interpolation was used for best estimation.	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Secondary	Duration of Plasma Concentrations of CP-70429 Exceeding 0.5 Microgram Per Milliliter Following PF-03709270 Oral Dose	Duration was calculated by subtracting the time at which the plasma concentrations exceeded 0.5 mcg/mL at the ascending part of the concentration-time profile from the time at which the plasma concentrations fell below 0.5 mcg/mL at the descending part of the profile. If these times fell between 2 observed concentrations, a method of linear interpolation was used for best estimation.	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Secondary	Duration of Plasma Concentrations of CP-70429 Exceeding 1.0 Microgram Per Milliliter Following Intravenous Dose	Duration was calculated by subtracting the time at which the plasma concentrations exceeded 1.0 mcg/mL at the ascending part of the concentration-time profile from the time at which the plasma concentrations fell below 1.0 mcg/mL at the descending part of the profile. If these times fell between 2 observed concentrations, a method of linear interpolation was used for best estimation.	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Secondary	Duration of Plasma Concentrations of CP-70429 Exceeding 1.0 Microgram Per Milliliter Following PF-03709270 Oral Dose	Duration was calculated by subtracting the time at which the plasma concentrations exceeded 0.5 mcg/mL at the ascending part of the concentration-time profile from the time at which the plasma concentrations fell below 0.5 mcg/mL at the descending part of the profile. If these times fell between 2 observed concentrations, a method of linear interpolation was used for best estimation.	0 (pre-dose), 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Secondary	Pharmacokinetics of CP-70429 and PF-03709270 Metabolites	PF-03709270 is an oral prodrug of CP-70,429. Upon oral absorption, PF-03709270 is rapidly hydrolyzed, yielding the active drug CP-70,429 and metabolites.	0.5, 2, 4, 8, 12, 24 hours post-dose (for all participants) and 48 hours post-dose (for participants with moderate and severe renal impairment)	No
Secondary	Concentration Versus Time Summary of 2-Ethylbutyric Acid	Concentration versus time summary was calculated by setting concentration values below the lower limit of quantification (LLQ =100 ng/mL) to zero. Summary statistics were not to be presented if number of observations above lower limit of quantification (NALQ) =0.	1, 3, 8 hours post-dose	No
Secondary	Concentration Versus Time Summary of Plasma Formate	Concentration versus time summary was calculated by setting concentration values below the lower limit of quantification (LLQ =100 ng/mL) to zero. Summary statistics were not to be presented if number of observations above lower limit of quantification (NALQ) =0.	1, 3, 8 hours post-dose	No
Secondary	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 7-10 days after last dose that were absent before treatment or that worsened relative to pre-treatment state.	Baseline up to 7-10 days after the last dose of study drug (up to 32 days)	Yes
Secondary	Number of Participants With Laboratory Abnormalities	Criteria for laboratory test abnormality: Hematology (hemoglobin, hematocrit, red blood corpuscles [RBC] count: less than [<]0.8*lower limit of normal [LLN], platelets: <0.5*LLN/greater than [>]1.75*upper limit of normal [ULN], leukocytes: <0.6*LLN or >1.5*ULN, lymphocytes, total neutrophils: <0.8*LLN or >1.2*ULN, basophils, eosinophil, monocytes: >1.2*ULN); Liver Function (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase: >0.3*ULN, total protein, albumin: <0.8*LLN or >1.2*ULN); total bilirubin, direct bilirubin, indirect bilirubin: >1.5*ULN; Renal Function (blood urea nitrogen, creatinine: >1.3*ULN, uric acid: >1.2*ULN); Electrolytes (sodium: <0.95*LLN or >1.05*ULN, potassium, chloride, calcium, bicarbonate: <0.9*LLN or >1.1*ULN; creatine kinase: >2.0*ULN; glucose fasting: <0.6*LLN or >1.5*ULN, urine white blood corpuscles [WBC] and RBC: greater than or equal to (>=) 6/High Power Field [HPF]).	Baseline up to 7-10 days after the last dose of study drug (up to 32 days)	Yes
Secondary	Number of Participants With Vital Sign Abnormalities	Criteria for vital signs abnormalities included supine/sitting pulse rate of <40 beats per minute (bpm) or >120 bpm, supine systolic blood pressure (SBP) of <90 millimeter of mercury (mmHg), >=30 mmHg maximum increase and decrease from baseline in same posture, supine diastolic blood pressure (DBP) of <50 mmHg, >=20 mmHg maximum increase and decrease from baseline in same posture, heart rate <=45 beats per minute (bpm) or >=120 bpm or decrease/increase of >=15 bpm.	Baseline up to 7-10 days after the last dose of study drug (up to 32 days)	Yes
Secondary	Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities	Criteria for abnormal ECG (12-lead) values were defined as: maximum PR interval >=300 millisecond (msec) and maximum increase of >=25 percent for baseline value of >200 msec and >=50% for baseline value of <=200 msec for PR interval, QRS interval >=200 msec; QT interval corrected using the Fridericia formula (QTcF) >=500 msec or increase of >45 msec.	Baseline up to 7-10 days after the last dose of study drug (up to 32 days)	Yes
Secondary	Number of Participants With Change From Baseline in Physical Examinations	Physical examination included examination of the skin, eyes, ears, throat, neck, and cardiac, respiratory, gastrointestinal and musculoskeletal systems. The examination assessed the participants for any potential changes in physical status, as determined by the investigator. Any untoward findings identified on physical exams conducted after the administration of the first dose of study medication was captured as an adverse event.	Baseline, 7-10 days after the last dose of study drug	Yes

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