A population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-Hodgkin's or Hodgkin's lymphoma.
In a pralatrexate phase I study, patients displayed a high incidence of mucositis of grades 3 and 4. Preliminary evaluations of the pharmacokinetics of the drug and its association with mucositis suggested that pralatrexate exposure (area under the concentration-time curve (AUC)) could be controlled with body size (e.g., weight or body surface area)-based dosing and that pretreatment with folic acid and vitamin B(12) might diminish the incidence and severity of mucositis. The study was amended, with revised dosing and vitamin B(12) administration. Data from 47 patients were evaluated using NONMEM. Weight and methylmalonic acid (MMA) level were predictive of pharmacokinetic (PK) variability. AUC and MMA level were positively correlated with the risk of developing mucositis. A lower AUC schedule with vitamin B(12) pretreatment may control mucositis without compromising efficacy. The covariates identified in this study are comparable with other antifolate analogs. The application of modeling was a critical step in the development of pralatrexate, yielding important suggestions for dose, scheduling, and pretreatment modifications.
Mould
D R
DR
Projections Research, Phoenixville, Pennsylvania, USA. drmould@attglobal.net
Sweeney
K
K
Duffull
S B
SB
Neylon
E
E
Hamlin
P
P
Horwitz
S
S
Sirotnak
F
F
Fleisher
M
M
Saunders
M E
ME
O'Connor
O A
OA
D000328:Adult; D000368:Aged; D000630:Aminopterin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D049628:Body Size; D004334:Drug Administration Schedule; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D006689:Hodgkin Disease / Q000188:drug therapy*; D006801:Humans; D015994:Incidence; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008764:Methylmalonic Acid; D008875:Middle Aged; D015233:Models, Statistical; D052016:Mucositis / Q000139:chemically induced / Q000517:prevention & control*; D011237:Predictive Value of Tests; D012008:Recurrence; D012720:Severity of Illness Index; D014805:Vitamin B 12 / Q000008:administration & dosage
C418863:10-propargyl-10-deazaaminopterin; D000970:Antineoplastic Agents; D015415:Biomarkers; D005493:Folic Acid Antagonists; D008764:Methylmalonic Acid; D000630:Aminopterin; D014805:Vitamin B 12