Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous diflomotecan in patients with advanced malignant tumours.
OBJECTIVE
To determine the maximum tolerated dose (MTD) of intravenous (iv) diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model.


METHODS
Twenty-four patients received a total of 75 cycles of iv diflomotecan that was administered as 20-min infusion, once every 3 weeks at escalating doses of 2, 4, 5, and 6 mg/m2. Haematological and non-haematological toxicities were evaluated. Plasma concentrations of diflomotecan were measured after the first drug administration.


RESULTS
Dose limiting toxicity (DLT) following the first cycle occurred in 12 patients and a total of 16 patients experienced DLT at some point in the trial. During the first cycle of treatment the number of patients in the 5 and 6 mg/m2 dose groups that experienced DLT was 3 of 4, and 3 of 3, respectively. Therefore, the dose of 5 mg/m2 was considered the MTD and the dose of 4 mg/m2 the recommended dose (RD). During the first cycle, 12 patients experienced DLT, six had either infection of haematological toxicity and eight complained of fatigue. The best response was a partial response in one patient treated at the 6 mg/m2 dose level. Disease stabilization was observed in seven patients (four patients treated at 4 mg/m2 and one patient at each dose level of 2, 5, and 6 mg/m2). The remaining patients had all progressive disease. The median time to progression for all patients was 5.9 weeks. Pharmacokinetics of diflomotecan was described with a three-compartmental model. Mean population parameter estimates of the apparent volume of distribution of the central compartment (V c) increased linearly with body surface area (BSA) as: V c (L) = 41.5 x (BSA/1.85), and the mean population estimate of the apparent volume of distribution of the shallow compartment was lower in females (29.5 vs 48.8 L). Computer simulations showed the lack of clinical significance of these covariates. The time course of the neutropenic response was adequately described by a semi-mechanistic model that includes cellular processes and drug effects.


CONCLUSIONS
The MTD and RD after a 20-min iv infusion of diflomotecan every 3 weeks are 4 and 5 mg/m2, respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m2 of diflomotecan was 0.86 x 10(9) /L neutrophil cell counts and 11 days, respectively.
Trocòniz
Iñaki F
IF
Department of Pharmacy, School of Pharmacy, University of Navarra, Pamplona, Spain.
Garrido
María J
MJ
Segura
Cristina
C
Cendrós
Josep-María
JM
Principe
Paola
P
Peraire
Concepción
C
Obach
Rosendo
R
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005602:France; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008954:Models, Biological; D015337:Multicenter Studies as Topic; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced*
D000970:Antineoplastic Agents; C424962:diflomotecan; D002166:Camptothecin