A Clinical Study to Evaluate the Effect of Renal Impairment on the Pharmacokinetics of Cebranopadol

A Non-randomized, Single-dose, Open-Label, Pharmacokinetic Study of Cebranopadol in Patients With Impaired Renal Function and Subjects With Normal Renal Function

The objective of this study was to evaluate the pharmacokinetics (PK), safety and tolerability profile of cebranopadol (GRT6005) in patients with varying degree of renal impairment and participants with normal renal function after an oral single dose administration.

This study was a Phase 1, multi-center, non-randomized, open-label, parallel group, single-dose study in up to 24 male and female patients with varying degree of renal impairment and participants with normal renal function.

Within 14 days before the administration of cebranopadol the general eligibility of the participants for the study was assessed according to the inclusion/exclusion criteria. Estimated glomerular filtration rate (eGFR) was determined according to the Modification of Diet in Renal Disease (MDRD) equation.

A treatment period from Day -1 to Day 8 was performed, with participant confinement to the study site from Day -1 to Day 6 and an outpatient visit on Day 8. A single dose of cebranopadol 200 μg was administered on Day 1. Multiple blood and urine samples were drawn for pharmacokinetic evaluations and safety laboratory monitoring. Additional blood samples were taken prior investigational medicinal product (IMP) administration to assess serum creatinine concentration and protein binding.

An End-of-Trial Visit was performed at the time, or within 7 days, of the final blood sample on Day 8 or at early withdrawal.

Inclusion Criteria:

Common criteria:

• Sign the informed consent form (ICF) and have the mental capability to understand it.
• Be male or female, aged 18 through 75 years.
• If female, have a negative result from a serum pregnancy test at screening and a negative result from a serum or urine pregnancy test on Day -1.
• If male, agree to use an effective method of contraception (i.e., condom plus diaphragm with spermicide or condom plus spermicide) and not have their partners become pregnant throughout the study, or have been sterilized for at least 1 year (with supporting documentation of the absence of sperm in the ejaculate postvasectomy).
• If female of childbearing potential, agree to use an effective method of contraception (i.e., condom plus diaphragm with spermicide, condom plus spermicide, or nonhormonal intrauterine device) and not become pregnant throughout the study. Females who are at least 2-years postmenopausal (with supporting documentation from an obstetrician/gynecologist) or who have had tubal ligation or hysterectomy (with supporting documentation from the physician who performed the surgery) will not be considered to be of childbearing potential.
• Be nonsmoking (never smoked or have not smoked within the previous 2 years) or light smokers (less than or equal to 10 cigarettes per day within the previous 3 months).
• Have a sitting pulse rate greater than or equal to 50 beats per minute (bpm) or less than or equal to 100 bpm during the vital sign assessment at screening.
• Have a body mass index (BMI) greater than or equal to 18 kilograms per square meter and less than or equal to 42 kilograms per square meter.

Participants with Renal Impairment:

• Have results of medical history, physical examination, and laboratory and other test results consistent with their degree of renal impairment, as determined by the Investigator.
• Have an estimated glomerular filtration rate (eGFR) of 60-89 mL/min/1.73m2 (Group I); 30-59 mL/min/1.73m2 (Group II); and 15-29 mL/min/1.73 m2 (Group III). The maximum allowable intra-subject variability based on the 2 determinations of eGFR at screening and Day -1 using the Modification of Diet in Renal Disease (MDRD) equation is +/- 30%. If eGFR falls in different categories at screening and on Day -1, the Day -1 eGFR will be used for assignment to the renal impaired group.
• If receiving concomitant medications to treat underlying diseases or medical conditions related to renal insufficiency, must be on stable dosages of these medications for at least 8 weeks before screening.

Participants with Normal Renal Function:

- Have an eGFR greater than or equal to 90 mL/min/1.73 m2 at screening and on Day -1. The maximum allowable intra-subject variability based on the 2 determinations of eGFR at screening and Day -1 using the MDRD equation is +/- 30 percent. If eGFR falls in different categories at screening and Day -1, the Day -1 eGFR will be used to assign participant to study group.

Exclusion Criteria:

Common criteria:

• Known hypersensitivity to cebranopadol or other opioids.
• Abnormal ECG results thought to be potentially clinically significant according to the Investigator, or QT prolongation (QTcF greater than or equal to 450 msec; uncorrected QT greater than 500 msec).
• Positive test results for anti-human immunodeficiency virus type 1, hepatitis B surface antigen, hepatitis B core antibodies, or anti-hepatitis C virus at screening.
• History of alcohol or other substance abuse within the previous 5 years.
• Positive test results for benzoylecgonine (cocaine), methadone, barbiturates, amphetamines, benzodiazepines, alcohol, cannabinoids, opiates, or phencyclidine at screening or Day -1.
• Participation in any other clinical investigation using an experimental drug requiring repeated blood or plasma draws within 60 days of investigational product (IP) administration.
• Participation in a blood or plasma donation program within 60 or 30 days, respectively, of IP administration.
• Consumption of caffeine within 48 hours or consumption of alcohol within 72 hours before administration of IP.
• Consumption of beverages or food containing quinine (bitter lemon, tonic water) or any grapefruit-containing products, Seville oranges, or poppy seeds within 14 days before administration of IP.
• Any clinical condition or previous surgery that might affect the absorption, distribution, biotransformation, or excretion of cebranopadol.
• Employee, or immediate relative of an employee, of Forest Laboratories, Inc., any of its affiliates or partners, or the study center.
• Previously taken cebranopadol or previously participated in an investigational study of cebranopadol, unless otherwise authorized by the sponsor.
• Breastfeeding.

Participants with Renal Impairment:

• Clinically significant disease state, in the opinion of the examining physician, in any body system (other than renal function impairment or concomitant conditions for participants in groups I-III). Medical history, physical examination findings, and abnormal findings on electrocardiogram (ECG) and laboratory analyses should be reviewed, and the participant judged acceptable for participation in this study by the Investigator and Forest Medical Monitor.
• Sitting systolic blood pressure (BP) greater than or equal to 165 mm Hg or less than or equal to 95 mm Hg or sitting diastolic BP greater than or equal to 90 mm Hg or less than or equal to 50 mm Hg at screening.
• Abnormal and clinically significant results on physical examination, medical history, serum chemistry, hematology, or urinalysis with the exception of findings that are related to the renal disease process.
• Have undergone renal transplantation or had renal carcinoma within 1 year before screening.
• Have any evidence of skin lesions, diabetic foot, clinically significant edema states not judged to be related to renal failure, peripheral arterial disease, or epilepsy. (Edema [1+ to 3+ pitting] is allowed).
• History of or risks for acute pancreatitis or exacerbation of pancreatitis.
• Have taken any concomitant medications, with the exception of those medications prescribed as standard therapy for renal disease or other stable concomitant conditions, including over-the-counter medications, within 14 days before IP administration or hormonal drug products (except thyroid supplements) within 30 days before IP administration.

Participants with Normal Renal Function:

• Clinically significant disease state, in the opinion of the examining physician, in any body system.
• Sitting systolic BP greater than or equal to 140 mm Hg or less than or equal to 90 mm Hg or sitting diastolic BP greater than or equal to 90 mm Hg or less than or equal to 50 mm Hg at screening.
• Abnormal and clinically significant results on physical examination, medical history, oxygen saturation, serum chemistry, hematology, or urinalysis.
• Taken any concomitant medications (including over-the-counter medications) within 14 days or hormonal drug products (except thyroid supplements) within 30 days before administration of IP.