A phase I, open-label, multicenter study to evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and varying degrees of renal function.
OBJECTIVE
This study assessed the pharmacokinetics and safety of oral panobinostat and its metabolite BJB432 in patients with advanced solid tumors and normal to severely impaired renal function.


METHODS
Patients with varying degrees of renal impairment, defined by their 24-h baseline urine creatinine clearance (as normal, mild, moderate or severe), received a single oral dose of 30 mg panobinostat. Serial plasma samples were collected pre-dose and up to 96-h post-dose. Serial urine samples were collected for 24-h post-dose. Following the serial PK sampling, patients received 30 mg oral panobinostat thrice weekly for as long as the patient had benefit. Pharmacokinetic parameters were derived using non-compartmental analysis.


RESULTS
Thirty-seven patients were enrolled, and median age was 64 (range 40-81) years. Eleven patients had normal renal function; 10, 10, and 6 patients had mild, moderate, and severe renal impairment, respectively. Geometric means of AUC(0-∞) in the normal, mild, moderate, and severe groups were 224.5, 144.3, 223.1, and 131.7 ng h/mL, respectively. Geometric mean ratio of BJB432 to parent drug plasma AUC(0-∞) was 0.64 in the normal group and increased to 0.81, 1.13, and 1.20 in the mild, moderate, and severe groups, respectively. The fraction excreted as unchanged panobinostat was small (<2 %), with a large variability. The renal clearance of panobinostat and tolerability was similar across all four groups.


CONCLUSIONS
Systemic exposure to panobinostat did not increase with severity of renal impairment, and the drug was tolerated equally; thus, patients with renal impairment do not require starting dose adjustments.
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Sunil
S
Sharma
Petronella O
PO
Witteveen
Martijn P
MP
Lolkema
Dagmar
D
Hess
Hans
H
Gelderblom
Syed A
SA
Hussain
Maria G
MG
Porro
Edward
E
Waldron
Sue-Zette
SZ
Valera
Song
S
Mu
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001711:Biotransformation; D016903:Drug Monitoring; D015507:Drugs, Investigational / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007211:Indoles / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D060787:Neoplasm Grading; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000077767:Panobinostat; D010352:Patient Dropouts; D051437:Renal Insufficiency / Q000150:complications* / Q000503:physiopathology; D012720:Severity of Illness Index
D000970:Antineoplastic Agents; C000595676:BJB432; D015507:Drugs, Investigational; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat