Pharmacokinetic and pharmacodynamic evaluation of the glycinamide ribonucleotide formyltransferase inhibitor AG2034.
Glycinamide ribonucleotide formyltransferase (GARFT) is a component of the de novo purine synthesis pathway. AG2034 is a specific inhibitor of GARFT that was designed based on the GARFT crystal structure. In conjunction with Phase I studies at four clinical centers in the United States and United Kingdom, AG2034 pharmacology was evaluated in 54 patients receiving 1-11 mg/m2 AG2034 as a 2-5 min injection. Blood samples were obtained just prior to and 5, 15, 30, and 45 min, and 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, and 96 h after bolus injection during course 1. Limited sampling was also performed on course 3. Plasma AG2034 was measured using a sensitive and reproducible ELISA assay. AG2034 demonstrated a trimodal elimination pattern over 24 h, with median half-life (t(1/2))alpha = 8.7 min, t(1/2)beta = 72.6 min, and t(1/2)gamma = 364.2 min. AG2034 systemic clearance ranged from 9.4-144.5 ml/min/m2, and volume of distribution was 1.2-7.6 liters/m2. Course 1 AG2034 area under the concentration versus time curve (AUC) had a linear relationship with dose (r(s) = 0.86). Accumulation of AG2034 was evident, because course 3 AUC was higher than course 1 in 23 of 23 evaluable patients, but was not associated with an increase in erythrocyte AG2034. AG2034 systemic exposure had an impact on toxicity, because course 1 and course 3 AG2034 AUCs were significantly higher for patients with grade III/IV toxicity than patients with less than grade II toxicity (P < 0.001 and P = 0.001 for course 1 and course 3, respectively). This study demonstrates rapid systemic clearance of AG2034 and suggests pharmacokinetic approaches that may minimize patient toxicity and aid the development of this interesting class of anticancer agents.
Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, United Kingdom. h.l.mcleod@abdn.ac.uk
H L
HL
McLeod
J
J
Cassidy
R H
RH
Powrie
D G
DG
Priest
M A
MA
Zorbas
T W
TW
Synold
S
S
Shibata
D
D
Spicer
D
D
Bissett
Y K
YK
Pithavala
M A
MA
Collier
L J
LJ
Paradiso
J D
JD
Roberts
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000037:antagonists & inhibitors; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D051026:Phosphoribosylglycinamide Formyltransferase; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D012044:Regression Analysis; D006113:United Kingdom; D014481:United States
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005971:Glutamates; D011743:Pyrimidines; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; C105066:AG 2034