Population pharmacokinetics of HM781-36 (poziotinib), pan-human EGF receptor (HER) inhibitor, and its two metabolites in patients with advanced solid malignancies.
OBJECTIVE
To develop a population pharmacokinetic (PK) model for HM781-36 (poziotinib) and its metabolites in cancer patients.


METHODS
Blood samples were collected from three phase I studies in which fifty-two patients received oral HM781-36B tablets (0.5-32 mg) once daily for 2 weeks, and another 20 patients received oral HM781-36B tablets (12, 16, 18, 24 mg) in fasting (12 patients) or fed (eight patients) state once daily for 4 weeks. Nonlinear mixed effect modeling was employed to develop the population pharmacokinetic model.


RESULTS
HM781-36 PK was ascribed to a two-compartment model and HM781-36-M1/-M2 PK to one-compartment model. HM781-36 oral absorption was characterized by first-order input (absorption rate constant: 1.45 ± 0.23 h⁻¹). The central volume of distribution (185 ± 12.7 L) was influenced significantly by body weight. The absorption rate constant was influenced by food. The typical HM781-36 apparent clearance was 34.5 L/h (29.4 %CV), with an apparent peripheral volume of distribution of 164 L (53.5 %CV). Other covariates did not significantly further explain the PKs of HM781-36.


CONCLUSIONS
The proposed model suggests that HM781-36 PKs are consistent across most solid tumor types, and that the absorption process of HM781-36 is affected by the fed state before dosing. HM781-36 PKs are not complicated by patient factors, other than body weight.
Department of Clinical Pharmacology, Busan Paik Hospital, Inje University, Busan, Korea.
Yook-Hwan
YH
Noh
Hyeong-Seok
HS
Lim
Jin-A
JA
Jung
Tae Hun
TH
Song
Kyun-Seop
KS
Bae
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation; D007408:Intestinal Absorption; D008297:Male; D008657:Metabolic Clearance Rate; D008745:Methylation; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013607:Tablets
D000970:Antineoplastic Agents; D015507:Drugs, Investigational; C557213:HM781-36B; D011799:Quinazolines; D013607:Tablets; C512478:EGFR protein, human; D066246:ErbB Receptors