Clinical pharmacology of anticancer agents in relation to formulations and administration routes

Terwogt, Jetske M. Meerum; Schellens, Jan H.M.; Huinink, W.W. ten Bokkel; Beijnen, Jos H.

doi:10.1053/ctrv.1998.0107

Cited by 57 publications

(24 citation statements)

References 145 publications

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“…In common with other phase-specific cytotoxic agents, Ro 31-7453 showed more pronounced antitumor activity with protracted exposure in experimental models (5,7). Prolonged exposure, either by continuous infusion or oral administration (10), also avoids the possibility of excessive toxicity from high peak drug concentrations and may increase the therapeutic index. Oral treatment is clearly preferred by patients (11), and animal data using a novel oral sustained release microprecipitate formulation of Ro 31-7453 (8) supported exploration of this route of administration in humans.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Clinical and Pharmacokinetic Study of Ro 31-7453 Given as a 7- or 14-Day Oral Twice Daily Schedule Every 4 Weeks in Patients with Solid Tumors

Salazar

Bissett

Twelves

et al. 2004

Clinical Cancer Research

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Purpose: This is a dose-finding Phase I study of oral Ro 31-7453, a new class of antimitotic drug with promising preclinical activity in several chemoresistant models.Experimental Design: Two schedules of oral Ro 31-7453 (every 12 h) given for either 7 or 14 consecutive days repeated every 4 weeks were explored consecutively.Results: Thirty-seven patients with refractory cancer entered the study (14 on the 7-day schedule and 23 on the 14-day schedule). Median age was 63 years (range, 40 -77 years), and median Karnofsky performance status was 80 (range, 60 -100); the most frequent diagnosis was colorectal carcinoma (16 patients). Dose levels of 100, 200, 240, and 280 mg/m 2 twice daily (bid) for 7 days and 70, 100, 125, and 150 mg/m 2 bid for 14 days were explored. A total of 110 cycles were administered, the median number of cycles received was 3 (range, 1-7); six patients completed 6 or more cycles. Myelosuppression and mucositis were dose-limiting with both schedules. Fatigue and gastrointestinal toxicities other than mucositis were frequent but generally mild. The maximum tolerated doses were 200 mg/m 2 bid and 125 mg/m 2 bid for the 7-and 14-day schedules, respectively. Pharmacokinetic analysis showed rapid absorption and metabolism. The area under the concentration-time curve and trough concentrations of Ro 31-7453 and two active metabolites appeared dose proportional with a t 1/2 of ϳ9 h and a t max of ϳ4 h. One patient with pretreated lung cancer had a partial response. Conclusions: Both Ro 31-7453 regimens were feasible, but the 14-day schedule at the recommended dose of 125 mg/m 2 bid was selected for further monotherapy Phase II evaluation because of its higher preclinical activity. This regimen is convenient, well tolerated, and has a favorable pharmacokinetic profile.

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Section: Discussionmentioning

confidence: 99%

A Phase I Clinical and Pharmacokinetic Study of Ro 31-7453 Given as a 7- or 14-Day Oral Twice Daily Schedule Every 4 Weeks in Patients with Solid Tumors

Salazar

Bissett

Twelves

et al. 2004

Clinical Cancer Research

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“…In addition, oral administration facilitates prolonged exposure to a cytotoxic agent. 91 However, low solubility in aqueous fluids, low apparent permeability, and poor bioavailability are noted as limitations for oral chemotherapy. 92,93 Intravenous administration is the most direct, and it overcomes the variable absorption patterns of the gastrointestinal tract.…”

Section: Oral Cancer Treatmentmentioning

confidence: 99%

Nanotechnology-based drug delivery systems for treatment of oral cancer: a review

Calixto¹,

Fonseca-Santos²,

Chorilli³

et al. 2014

IJN

151

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Oral cancer (oral cavity and oropharynx) is a common and aggressive cancer that invades local tissue, can cause metastasis, and has a high mortality rate. Conventional treatment strategies, such as surgery and chemoradiotherapy, have improved over the past few decades; however, they remain far from optimal. Currently, cancer research is focused on improving cancer diagnosis and treatment methods (oral cavity and oropharynx) nanotechnology, which involves the design, characterization, production, and application of nanoscale drug delivery systems. In medicine, nanotechnologies, such as polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, gold nanoparticles, hydrogels, cyclodextrin complexes, and liquid crystals, are promising tools for diagnostic probes and therapeutic devices. The objective of this study is to present a systematic review of nanotechnology-based drug delivery systems for oral cancers.

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“…Treatment advances have also been made by modulating drug administration schedules and routes (e.g., the introduction of i.v. or intra-arterial administration) [Terwogt et al 1999], changing drug formulation (e.g., by encapsulating chemotherapeutic drugs in liposomes or binding them to polymers) [Terwogt et al 1999], and introducing new drug combinations (e.g., Herceptin plus taxanes) [Slamon et al 2001]. Both alone and combined, these strategies are proving successful in improving cancer survival and cure rates [Ferrante et al 1999;Greco and Hainsworth 1999;Miller and Sledge 1999;Rich 1999].…”

Section: Introductionmentioning

confidence: 99%

“…New drug development requires extensive and thorough optimization of drug formulation, route of administration and selection of combination therapy [de Valerio-32 Oncology 2001;61(suppl 2):31-36 Leyland-Jones la et Masson et al 1997;Terwogt et al 1999]. The pharmacology and pharmacokinetics of new drugs must also be well characterized [Masson et al 1997;Terwogt et al 1999].…”

Section: Introductionmentioning

confidence: 99%

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Dose Scheduling – Herceptin<sup>®</sup>

Leyland‐Jones

2001

Oncology

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Preclinical and phase I/II studies of Herceptin^® demonstrated a dose-related, non-linear pharmacokinetic profile. The results of a dose-finding study supported a regimen comprising an initial intravenous (i.v.) dose of 4 mg/kg with subsequent weekly doses of 2 mg/kg. However, pharmacokinetic and safety data suggested that increased dose and reduced frequency of Herceptin administration are feasible. In addition, evidence shows that Herceptin plus paclitaxel has additive antitumor efficacy in vitro, and this regimen produces significant clinical benefits. These observations form the rationale for conducting a phase I/II trial of Herceptin (8 mg/kg initial dose, 6 mg/kg maintenance dose) plus paclitaxel, both given 3-weekly. Preliminary results are promising, with serum trough Herceptin concentrations being similar and AUC being greater than those observed with weekly Herceptin plus 3-weekly paclitaxel. Two further trials are proposed: 3-weekly Herceptin as first-line monotherapy of metastatic breast cancer; and 3-weekly Herceptin with the oral 5-fluorouracil derivative, Xeloda^® (capecitabine). Subcutaneous (s.c.) administration of Herceptin would further simplify administration and studies are also underway to clinically evaluate s.c. administration of Herceptin in combination with paclitaxel. With the recent development of oral taxanes, it is predicted that combinations including an oral taxane, Xeloda and either 3-weekly or possibly s.c. Herceptin may become future therapies for breast cancer patients.

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Clinical pharmacology of anticancer agents in relation to formulations and administration routes

Cited by 57 publications

References 145 publications

A Phase I Clinical and Pharmacokinetic Study of Ro 31-7453 Given as a 7- or 14-Day Oral Twice Daily Schedule Every 4 Weeks in Patients with Solid Tumors

A Phase I Clinical and Pharmacokinetic Study of Ro 31-7453 Given as a 7- or 14-Day Oral Twice Daily Schedule Every 4 Weeks in Patients with Solid Tumors

Nanotechnology-based drug delivery systems for treatment of oral cancer: a review

Dose Scheduling – Herceptin<sup>®</sup>

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