Time-dependent kinetics of tretinoin in chronic myelogenous leukaemia during intermittent dose scheduling. 1 week on/1 week off

M. B. Regazzi, D. Russo, I. Iacona, S. Sacchi, G. Visani, M. Lazzarino, G. Avvisati, P. G. Pelicci, G. Dastoli, C. Grandi, S. Spreafico, R. Grattoni, P. Galieni, S. Rupoli, A. M. Maiolo, E. Guerra, A. M. Liberati

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Abstract

Objective: This study investigated the pharmacokinetics of tretinoin during alternating cycles of 1 week of tretinoin treatment and 1 week drug-free in patients with PhI+ chronic myelogenous leukaemia (CML) in the chronic phase. Patients: Eighteen patients with CML were treated with tretinoin 80 mg/m2/day (in two divided doses) for 7 consecutive days every other week (one cycle = 1 week on/1 week off). Results: Body systemic exposure to tretinoin as determined by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from (mean ± SD) 678.3 ± 498.1 to 258.7 ± 272.4 μg/L · h. In about 40% of the patients the decline in plasma concentrations was ≤ 80%, while 17% of the population did not experience any decline. On day 7 of cycle 1, the mean apparent oral clearance (CL/F) was 2.6 times the corresponding value on day 1. After 1 week without tretinoin, the mean AUC on day 1 of cycle 2 was lower (down 15%) but not statistically different from the corresponding value observed on day 1 of cycle 1; 62% of patients showed an increase in the AUC, which was 40% higher than the corresponding value on day 7 of cycle 1. On day 1 of cycle 6, the AUC and CL/F of tretinoin during a dosage interval were not statistically different from those observed on day 1 of cycle 1 and cycle 2. On all occasions the peak plasma concentration (C(max)) was strongly correlated to the corresponding AUC. No significant change in the time to observed C(max) (t(max)) and in the elimination half-life (t( 1/4 )) was observed during the whole study. These results confirmed that the metabolism of tretinoin is rapidly up-regulated in CML patients, with significant declines in plasma drug exposure during the first week of drug administration. After tretinoin was discontinued, a return to the non-induced state followed a mean time-cycle similar to the induction. The strong decrease in the apparent oral drug clearance and the absence of significant variations in the drug half-life demonstrated that the presystemic extraction of tretinoin is the main cause of the marked decline in plasma drug exposure. Conclusion: The favourable pharmacokinetic profile of tretinoin obtained by an intermittent regimen, 1 week on/1 week off therapy (vs continuous administration), suggests that such a therapeutic schedule is the most appropriate for the assessment of clinical efficacy in those pathologies in which its use is suitable.

Original languageEnglish
Pages (from-to)25-33
Number of pages9
JournalClinical Drug Investigation
Volume16
Issue number1
DOIs
Publication statusPublished - 1998

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Tretinoin
Area Under Curve
Pharmaceutical Preparations
Half-Life
Pharmacokinetics
Leukemia, Myeloid, Chronic Phase
Appointments and Schedules
Therapeutics
Pathology

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

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Time-dependent kinetics of tretinoin in chronic myelogenous leukaemia during intermittent dose scheduling. 1 week on/1 week off. / Regazzi, M. B.; Russo, D.; Iacona, I.; Sacchi, S.; Visani, G.; Lazzarino, M.; Avvisati, G.; Pelicci, P. G.; Dastoli, G.; Grandi, C.; Spreafico, S.; Grattoni, R.; Galieni, P.; Rupoli, S.; Maiolo, A. M.; Guerra, E.; Liberati, A. M.

In: Clinical Drug Investigation, Vol. 16, No. 1, 1998, p. 25-33.

Research output: Contribution to journalArticle

Regazzi, MB, Russo, D, Iacona, I, Sacchi, S, Visani, G, Lazzarino, M, Avvisati, G, Pelicci, PG, Dastoli, G, Grandi, C, Spreafico, S, Grattoni, R, Galieni, P, Rupoli, S, Maiolo, AM, Guerra, E & Liberati, AM 1998, 'Time-dependent kinetics of tretinoin in chronic myelogenous leukaemia during intermittent dose scheduling. 1 week on/1 week off', Clinical Drug Investigation, vol. 16, no. 1, pp. 25-33. https://doi.org/10.2165/00044011-199816010-00004
Regazzi, M. B. ; Russo, D. ; Iacona, I. ; Sacchi, S. ; Visani, G. ; Lazzarino, M. ; Avvisati, G. ; Pelicci, P. G. ; Dastoli, G. ; Grandi, C. ; Spreafico, S. ; Grattoni, R. ; Galieni, P. ; Rupoli, S. ; Maiolo, A. M. ; Guerra, E. ; Liberati, A. M. / Time-dependent kinetics of tretinoin in chronic myelogenous leukaemia during intermittent dose scheduling. 1 week on/1 week off. In: Clinical Drug Investigation. 1998 ; Vol. 16, No. 1. pp. 25-33.
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abstract = "Objective: This study investigated the pharmacokinetics of tretinoin during alternating cycles of 1 week of tretinoin treatment and 1 week drug-free in patients with PhI+ chronic myelogenous leukaemia (CML) in the chronic phase. Patients: Eighteen patients with CML were treated with tretinoin 80 mg/m2/day (in two divided doses) for 7 consecutive days every other week (one cycle = 1 week on/1 week off). Results: Body systemic exposure to tretinoin as determined by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from (mean ± SD) 678.3 ± 498.1 to 258.7 ± 272.4 μg/L · h. In about 40{\%} of the patients the decline in plasma concentrations was ≤ 80{\%}, while 17{\%} of the population did not experience any decline. On day 7 of cycle 1, the mean apparent oral clearance (CL/F) was 2.6 times the corresponding value on day 1. After 1 week without tretinoin, the mean AUC on day 1 of cycle 2 was lower (down 15{\%}) but not statistically different from the corresponding value observed on day 1 of cycle 1; 62{\%} of patients showed an increase in the AUC, which was 40{\%} higher than the corresponding value on day 7 of cycle 1. On day 1 of cycle 6, the AUC and CL/F of tretinoin during a dosage interval were not statistically different from those observed on day 1 of cycle 1 and cycle 2. On all occasions the peak plasma concentration (C(max)) was strongly correlated to the corresponding AUC. No significant change in the time to observed C(max) (t(max)) and in the elimination half-life (t( 1/4 )) was observed during the whole study. These results confirmed that the metabolism of tretinoin is rapidly up-regulated in CML patients, with significant declines in plasma drug exposure during the first week of drug administration. After tretinoin was discontinued, a return to the non-induced state followed a mean time-cycle similar to the induction. The strong decrease in the apparent oral drug clearance and the absence of significant variations in the drug half-life demonstrated that the presystemic extraction of tretinoin is the main cause of the marked decline in plasma drug exposure. Conclusion: The favourable pharmacokinetic profile of tretinoin obtained by an intermittent regimen, 1 week on/1 week off therapy (vs continuous administration), suggests that such a therapeutic schedule is the most appropriate for the assessment of clinical efficacy in those pathologies in which its use is suitable.",
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T1 - Time-dependent kinetics of tretinoin in chronic myelogenous leukaemia during intermittent dose scheduling. 1 week on/1 week off

AU - Regazzi, M. B.

AU - Russo, D.

AU - Iacona, I.

AU - Sacchi, S.

AU - Visani, G.

AU - Lazzarino, M.

AU - Avvisati, G.

AU - Pelicci, P. G.

AU - Dastoli, G.

AU - Grandi, C.

AU - Spreafico, S.

AU - Grattoni, R.

AU - Galieni, P.

AU - Rupoli, S.

AU - Maiolo, A. M.

AU - Guerra, E.

AU - Liberati, A. M.

PY - 1998

Y1 - 1998

N2 - Objective: This study investigated the pharmacokinetics of tretinoin during alternating cycles of 1 week of tretinoin treatment and 1 week drug-free in patients with PhI+ chronic myelogenous leukaemia (CML) in the chronic phase. Patients: Eighteen patients with CML were treated with tretinoin 80 mg/m2/day (in two divided doses) for 7 consecutive days every other week (one cycle = 1 week on/1 week off). Results: Body systemic exposure to tretinoin as determined by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from (mean ± SD) 678.3 ± 498.1 to 258.7 ± 272.4 μg/L · h. In about 40% of the patients the decline in plasma concentrations was ≤ 80%, while 17% of the population did not experience any decline. On day 7 of cycle 1, the mean apparent oral clearance (CL/F) was 2.6 times the corresponding value on day 1. After 1 week without tretinoin, the mean AUC on day 1 of cycle 2 was lower (down 15%) but not statistically different from the corresponding value observed on day 1 of cycle 1; 62% of patients showed an increase in the AUC, which was 40% higher than the corresponding value on day 7 of cycle 1. On day 1 of cycle 6, the AUC and CL/F of tretinoin during a dosage interval were not statistically different from those observed on day 1 of cycle 1 and cycle 2. On all occasions the peak plasma concentration (C(max)) was strongly correlated to the corresponding AUC. No significant change in the time to observed C(max) (t(max)) and in the elimination half-life (t( 1/4 )) was observed during the whole study. These results confirmed that the metabolism of tretinoin is rapidly up-regulated in CML patients, with significant declines in plasma drug exposure during the first week of drug administration. After tretinoin was discontinued, a return to the non-induced state followed a mean time-cycle similar to the induction. The strong decrease in the apparent oral drug clearance and the absence of significant variations in the drug half-life demonstrated that the presystemic extraction of tretinoin is the main cause of the marked decline in plasma drug exposure. Conclusion: The favourable pharmacokinetic profile of tretinoin obtained by an intermittent regimen, 1 week on/1 week off therapy (vs continuous administration), suggests that such a therapeutic schedule is the most appropriate for the assessment of clinical efficacy in those pathologies in which its use is suitable.

AB - Objective: This study investigated the pharmacokinetics of tretinoin during alternating cycles of 1 week of tretinoin treatment and 1 week drug-free in patients with PhI+ chronic myelogenous leukaemia (CML) in the chronic phase. Patients: Eighteen patients with CML were treated with tretinoin 80 mg/m2/day (in two divided doses) for 7 consecutive days every other week (one cycle = 1 week on/1 week off). Results: Body systemic exposure to tretinoin as determined by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from (mean ± SD) 678.3 ± 498.1 to 258.7 ± 272.4 μg/L · h. In about 40% of the patients the decline in plasma concentrations was ≤ 80%, while 17% of the population did not experience any decline. On day 7 of cycle 1, the mean apparent oral clearance (CL/F) was 2.6 times the corresponding value on day 1. After 1 week without tretinoin, the mean AUC on day 1 of cycle 2 was lower (down 15%) but not statistically different from the corresponding value observed on day 1 of cycle 1; 62% of patients showed an increase in the AUC, which was 40% higher than the corresponding value on day 7 of cycle 1. On day 1 of cycle 6, the AUC and CL/F of tretinoin during a dosage interval were not statistically different from those observed on day 1 of cycle 1 and cycle 2. On all occasions the peak plasma concentration (C(max)) was strongly correlated to the corresponding AUC. No significant change in the time to observed C(max) (t(max)) and in the elimination half-life (t( 1/4 )) was observed during the whole study. These results confirmed that the metabolism of tretinoin is rapidly up-regulated in CML patients, with significant declines in plasma drug exposure during the first week of drug administration. After tretinoin was discontinued, a return to the non-induced state followed a mean time-cycle similar to the induction. The strong decrease in the apparent oral drug clearance and the absence of significant variations in the drug half-life demonstrated that the presystemic extraction of tretinoin is the main cause of the marked decline in plasma drug exposure. Conclusion: The favourable pharmacokinetic profile of tretinoin obtained by an intermittent regimen, 1 week on/1 week off therapy (vs continuous administration), suggests that such a therapeutic schedule is the most appropriate for the assessment of clinical efficacy in those pathologies in which its use is suitable.

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