Adaptive control of etoposide administration: Impact of interpatient pharmacodynamic variability

Ratain, Mark J.; Schilsky, Richard L.; Choi, Kyung Jun; Guarnieri, Carol; Grimmer, D; Vogelzang, Nicholas J.; Senekjian, Elizabeth K.; Liebner, Mary Ann

doi:10.1038/clpt.1989.22

Cited by 85 publications

(19 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This approach has yielded a decrease in intrapatient and interpatient variability in haematological toxicity in patients treated with i.v. etoposide [40,41]. TDM-guided dose individualization of methotrexate, teniposide and cytarabine has permitted the safe increase drug exposure in children with leukaemia [42], resulting in a signi®cant improvement in disease free as compared with conventional therapy.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics and pharmacodynamics of oral etoposide

Toffoli

Corona

Sorio

et al. 2001

Brit J Clinical Pharma

View full text Add to dashboard Cite

Aims To study the population pharmacokinetics and pharmacodynamics of oral etoposide in patients with solid tumours.Methods A prospective, open label, cross‐over, bioavailability study was performed in 50 adult patients with miscellaneous, advanced stage solid tumours, who were receiving oral (100 mg capsules) etoposide for 14 days and i.v. (50 mg) etoposide on day 1 or day 7 in randomised order during the first cycle treatment. Total and unbound etoposide concentration were assayed by h.p.l.c. Population PK parameters estimation was done by using the P‐Pharm software (Simed). Haematological toxicity and tumour response were the main pharmacodynamic endpoints.Results Mean clearance was 1.14 l h−1 (CV 25%). Creatinine clearance was the only covariable to significantly reduce clearance variability (residual CV 18%). (CL = 0.74 + 0.0057 CLCR; r2 = 0.32). Mean bioavailability was 45% (CV 22%) and mean protein binding 91.5% (CV 5%). Exposure to free, pharmacologically active etoposide (free AUC p.o.) was highly variable (mean value 2.8 mg l−1 h; CV 64%; range 0.4–9.5). It decreased with increased creatinine clearance and increased with age which accounted for 9% of the CV. Mean free AUC p.o. was the best predictor of neutropenia. Free AUC50 (exposure producing a 50% reduction in absolute neutrophil count) was 1.80 mg l−1 h. In patients with lung cancer, the free AUC p.o. was higher in the two patients with responsive tumour (5.9 mg l−1 h) than in patients with stable (2.1 mg l−1 h) or progressive disease (2.3 mg l−1 h) (P = 0.01).Conclusions Exposure to free etoposide during prolonged oral treatment is highly variable and is the main determinant of pharmacodynamic effects. The population PK model based on creatinine clearance is poorly predictive of exposure. Therapeutic drug monitoring would be necessary for dose individualization or to study the relationship between exposure and antitumour effect.

show abstract

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics and pharmacodynamics of oral etoposide

Toffoli

Corona

Sorio

et al. 2001

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…This patient had a [5LCr]EDTA clearance, which was at the bottom of the normal range (59 ml min-' m-2) and the longest [5'Cr]EDTA elimination half-life (114 min vs 77±23 min), although no overt signs of renal impairment. It seems likely that the reduced interpatient pharmacokinetic variability seen in this group of patients was due to the fact that only one child had previously received cisplatin, as cisplatin therapy has previously been shown to predict for reduced etoposide clearance (Pfluger et al, 1987(Pfluger et al, , 1993Relling et al, 1994 Previous studies involving targeted dosing with etoposide using limited sampling methods have involved the administration of etoposide as a continuous infusion over 3 or 5 days (Ratain et al, 1989(Ratain et al, , 1991Joel et al, 1996). In addition, English et al (1996) reported two anephric paediatric patients in whom targeted dosing with both etoposide and carboplatin was possible using detailed pharmacokinetic sampling over three doses.…”

Section: Discussionmentioning

confidence: 99%

“…Adaptive control of etoposide dosing based upon both pharmacokinetic and pharmacodynamic factors has been used by Ratain et al (1989Ratain et al ( , 1991 to treat patients with small-cell lung cancer. In these latter studies, dosing in the adaptive control arm was based upon the pretreatment white cell count and the plasma etoposide concentration at 24 h, and the pharmacodynamic target was a chosen degree of haematological toxicity.…”

Section: Discussionmentioning

confidence: 99%

A study of the feasibility and accuracy of pharmacokinetically guided etoposide dosing in children

Lowis

Price²,

Pearson³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

Summary Pharmacokinetically guided dosing was performed in nine paediatric patients receiving etoposide. Doses on day 2 of a 2-or 3-day schedule were adapted on the basis of the day-1 area under the plasma etoposide concentration vs time curve (AUC). The day-1 AUC was estimated using a limited sampling model and the day-2 target AUC defined by the etoposide dose-AUC relationship observed in 33 children. Target AUC values (4.6-8.2 mg ml-1 x min) were achieved with a high degree of precision and with little bias (mean error 11% and root mean squared error 15% respectively). Pharmacokinetic parameters were similar to those reported previously in children, although interpatient pharmacokinetic variability was less than that observed previously: plasma clearance, 23 (18-26) ml min-' m-2; volume of distribution at steady state (Vdss), 6.0 (3.9-8.9) m-2; t,,2 254 (127-550) min (median and range). This study has demonstrated that pharmacokinetically guided dosing with etoposide is feasible. However, pharmacokinetically guided dosing is likely to be of most benefit in patients with abnormalities of renal or hepatic function, or in children with prior exposure to cisplatin.Keywords: etoposide; adaptive dosing; pharmacokinetics; children Etoposide is an active and widely used agent in paediatnic oncology.

show abstract

“…One approach to reduce this variability would be through adaptive control dosing strategies, in which drug concentrations are determined during or after drug administration, and subsequent doses adjusted to achieve a target concentration or drug exposure. That strategy has been effectively used for many regimens including etoposide, 47 topotecan, 48 and antimetabolites. 49 Unfortunately, generalized application of these approaches is limited by necessity for specialized personnel to perform drug quantitation and pharmacokinetic modeling.…”

Section: Figurementioning

confidence: 99%

Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukemia

et al. 2002

View full text Add to dashboard Cite

The purpose of this study was to assess the effect of the multidrug resistance modulator cyclosporine (CsA) on the pharmacokinetics of etoposide and mitoxantrone in children with de novo acute myeloid leukemia (AML). Serial blood samples for pharmacokinetic studies were obtained in 38 children over a 24-h period following cytotoxin treatment with or without CsA on days 1 and 4. Drug concentrations were quantitated using validated HPLC methods, and pharmacokinetic parameters were determined using compartmental modeling with an iterative two-stage approach, implemented on ADAPT II software. Etoposide displayed a greater degree of interindividual variability in clearance and systemic exposure than mitoxantrone. With CsA treatment, etoposide and mitoxantrone mean clearance declined by 71% and 42%, respectively. These effects on clearance, in combination with the empiric 40% dose reduction for either cytotoxin, resulted in a 47% and 12% increases in the mean AUC for etoposide and mitoxantrone, respectively. There were no differences in the rates of stomatitis or infection between the two groups. CsA treatment resulted in an increased incidence of hyperbilrubinemia, which rapidly reversed upon conclusion of drug therapy. The variability observed in clearance, combined with the empiric 40% dose reduction of the cytotoxins, resulted in statistically similar systemic exposure and similar toxicity. Leukemia (2002) 16, 920-927.

show abstract

Adaptive control of etoposide administration: Impact of interpatient pharmacodynamic variability

Cited by 85 publications

References 1 publication

Population pharmacokinetics and pharmacodynamics of oral etoposide

Population pharmacokinetics and pharmacodynamics of oral etoposide

A study of the feasibility and accuracy of pharmacokinetically guided etoposide dosing in children

Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukemia

Contact Info

Product

Resources

About