Anaemia
Conditions
Brief summary
This will be an open-label, parallel-group study to evaluate the pharmacokinetics of GSK1278863 and metabolites in normal subjects and subjects with impaired renal function, including those who are hemodialysis dependent. GSK1278863 will be administered once daily for 14 days to normal subjects and subjects with Stage 3 and Stage 4 renal function, and 15 days to subjects with Stage 5 renal function. Pharmacokinetic assessments will be made on Days 1 and 14 (normal subjects, subjects with Stage 3 and Stage 4 renal function) or Days 14 and 15 (dialysis and non-dialysis days; Stage 5).
Interventions
DRUG5 mg GSK1278863
5 mg per day administered orally for 14 days for normal subjects and subjects with Stage 3/4 renal function; 5 mg per day administered orally for 15 days for subjects with Stage 5 renal function
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
All Study Participants A subject will be eligible for inclusion in this study only if all of the following criteria apply: * Adults between 18 and 75 years of age at the time of Screening. * A female subject is eligible to participate if she is of childbearing potential, and must agree to use one of the contraception methods described in the protocol. This criterion must be followed from the time of Screening until completion of the Follow-up Visit. OR Non-childbearing potential as defined in the protocol. * Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods in the protocol. This criterion must be followed from the time of the first dose of investigational product until completion of the Follow-up visit. * Satisfactory medical evaluation based upon medical history, medication history, physical examination, and clinical laboratory data obtained at the screening visit. * Body weight ≥ 45 kg and ≤ 140 kg at screening. For Stage 5 subjects, body weight is dry weight after hemodialysis. * QTcF \< 450 msec; OR QTcF \< 480 msec in subjects with Bundle Branch Block. These should be based on average of triplicate values obtained over brief recording period at screening and Predose on Day 1. * Vitamin B12 and folate above the lower limit of normal at screening. * The subject is mentally and legally able to comply with the requirements and restrictions of the protocol and has provided signed informed consent prior to participation in any protocol-specific procedures, including screening procedures. Additional Inclusion Criteria for Subjects with Normal Renal Function * Has normal creatinine clearance (CLCR) via the Cockcroft-Gault equation, using serum creatinine and demographic data, obtained at Screening. Normal subjects should have no greater than trace blood or protein on Screening urinalysis. * A hemoglobin value at screening is greater than the lower limit of the reference range for the local laboratory and less than or equal to 16.0g/dL * No greater than trace blood on screening urinalysis * Laboratory values for which specific criteria are not defined within the inclusion and
Exclusion criteria
for this study must be within the normal range or deemed not clinically significant. A normal subject with a clinical abnormality or laboratory parameters outside the reference range may be included only if the investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures, or the integrity of the study. Additional Inclusion Criteria for Subjects with Renal Impairment * Has Stage 3 or Stage 4 renal function (not receiving dialysis) as determined by estimated Glomerular Filtration Rate (eGFR) calculated by the abbreviated MDRD equation OR has Stage 5 renal function (end-stage renal failure) and has been on stable hemodialysis treatment scheduled three times weekly for 3 months prior to screening and the serum creatinine value at the Day -1 visit must be within +/- 20% of the screening value. * Is otherwise considered clinically stable with respect to underlying renal impairment as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and ECG. * has clinical laboratory test results that are considered clinically stable in the opinion of the Investigator, especially if the clinical abnormality or laboratory parameter is deemed associated with the subject's underlying renal impairment. * has AST, ALT, alkaline phosphatase and bilirubin \< or = 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). * Meets the following erythropoiesis stimulating agent (ESA) criteria: The subject is ESA naïve OR the subject has a scheduled ESA interval which is ≤ 7 days, ESA treatment must be discontinued for at least 7 days OR the subject has a scheduled ESA interval which is \> 7 days, ESA treatment must be discontinued for at least that scheduled interval length (e.g. discontinued ≥ 14 days for a scheduled 14 day ESA interval) AND the subject will not resume ESA treatment until completion of the Follow-up Visit. * Has a hemoglobin value: For ESA naïve subjects: ≤11.0 g/dL or subjects receiving ongoing ESA treatment: ≤12.0 g/dL at screening with a re check value of ≤11.0 g/dL after appropriate ESA discontinuation according to the Inclusion criterion on use of ESAs and prior to commencing investigational product dosing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area under the concentration-time curve over the dosing interval . Composite of Pharmacokinetics | Blood samples will be collected at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72hr post dosing on Day 1 and Day 14 for normal and Stage3/4 subjects, and on Day 14 and Day 15 for Stage 5 subjects | Area under the concentration-time curve over the dosing interval of GSK1278863 and metabolites on Day 1 and Day 14 for normal subjects and subjects with Stage 3/4 renal function; Area under the concentration-time curve over the dosing interval of GSK1278863 and metabolites on Day 14 (dialysis) and Day 15 (non-dialysis) for subjects with Stage 5 renal function. |
| Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time. Composite of Pharmacokinetics | Blood samples will be collected at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72hr post dosing on Day 1 in normal and Stage3/4 subjects | Area under the concentration-time curve from time zero (pre-dose) of GSK1278863 and metabolites on Day 1 for normal subjects and subjects with Stage 3/4 renal functione-dose) extrapolated to infinite time for |
| Maximum observed concentration. Composite of Pharmacokinetics | Blood samples will be collected at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72hr post dosing on Day 1 and Day 14 for normal and Stage3/4 subjects, and on Day 14 and Day 15 for Stage 5 subjects | Maximum observed concentration of GSK1278863 and metabolites on Day 1 and Day 14 for normal subjects and subjects with Stage 3/4 renal function; Maximum observed concentration of GSK1278863 and metabolites on Day 14 and Day 15 for subjects with Stage 5 renal function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| renal clearance | Day 14 | renal clearance of GSK1278863 and metabolites in normal subjects and subjects with Stage 3/4 renal function |
| dialysis clearance | Day 14 | dialysis clearance of GSK1278863 and metabolites in Stage 5 renal function |
| Safety and tolerability as assessed by the number of adverse events during the dosing period. | For normal subjects and subjects with Stage 3/4 renal function, from Day 1 to the follow-up visit at approximately Day 27. For subjects with Stage 5 renal function, from Day 1 to the follow-up visit at approximately Day 28. | — |
| change from baseline in heart rate | For normal subjects and subjects with Stage 3/4 renal function, from Day 1 to the follow-up visit at approximately Day 27. For subjects with Stage 5 renal function, from Day 1 to the follow-up visit at approximately Day 28. | — |
| Safety and tolerability of GSK1278863 as assessed by change from baseline in toxicity grading of clinical laboratory tests | For normal subjects and subjects with Stage 3/4 renal function, from Day 1 to Day 15; For subjects with Stage 5 renal function, from Day 1 to Day 16. | — |
| change from baseline in QTcB or QTcF | For normal subjects and subjects with Stage 3/4 renal function, from Day 1 to Day 14; For subjects with Stage 5 renal function, from day 1 to day 15. | — |
| Time of occurrence of maximum observed concentration | Day 1 and Day 14 | Time of occurrence of maximum observed concentration of GSK1278863 and metabolites on Day 1 and Day 14 for normal subjects and subjects with Stage 3/4 renal function |
| Terminal phase half-life | Day 1 and Day 14 | Terminal phase half-life of GSK1278863 and metabolites on Day 1 and Day 14 for normal subjects and subjects with Stage 3/4 renal function |
Countries
United States
Outcome results
None listed