Biomedical subjects

L J van Warmerdam

Publications and source records attributed to L J van Warmerdam.

At least 19 recordsLinked to original sources

PubMed2000

Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous infusion.

Docetaxel, a taxane antitumor agent, was administered to 24 patients by a 1-h intravenous infusion at a dose level of 100 mg/m(2) with pharmacokinetic monitoring. The plasma concentration-versus-time data were fitted with a three-compartment model. The mean area under the curve (AUC) for docetaxel was 3.1 +/- 0.9 h. mg/l and the clearance was 34.8 +/- 9.3 l/h per m(2). There was considerable interpatient pharmacokinetic variability. In 33% of the patient population, metabolites were detected in plasma samples collected 5-30 min after the end of the infusion. The cyclized oxazolidinedione metabolite M4 was most frequently present and was detected in 8 out of 24 patients with maximal concentrations between 0.022 and 0.23 mg/l. Logistic regression analysis was performed to predict M4 docetaxel metabolism. In the final model, alanine aminotransferase and alkaline phosphatase levels were the strongest predictors. No relationship was found between M4 metabolism and percentage decrease in neutrophil count in this study. Three patients with high M4 concentrations in plasma during course 1 suffered from most pronounced fluid retention (grade 2-3) after two to five courses.

Adult↗

PubMed1999

A single 24-hour plasma sample does not predict the carboplatin AUC from carboplatin-paclitaxel combinations or from a high-dose carboplatin-thiotepa-cyclophosphamide regimen.

PURPOSE: It has been observed that the area under the free carboplatin concentration in plasma ultrafiltrate versus time curve (AUC) is related to toxicity and tumour response. For this reason, it can be important to measure the carboplatin AUC and subsequently adjust the dose to achieve a predefined target AUC. The use of limited sampling strategies enables relatively simple measurement and calculation of actual carboplatin AUCs. METHODS: We studied the performance of a limited sampling model, based on a single 24-h sample (the Ghazal-Aswad model). in 52 patients who received carboplatin in two different chemotherapy regimens (a carboplatin-paclitaxel combination and a high-dose carboplatin-thiotepa-cyclophosphamide combination). RESULTS: The measured mean AUC in our population was 4.1 min x mg/ml (median 3.9, range 1.9 6.3, SD 1.0 min x mg/ml). With the limited sampling model, the predicted mean AUC was 4.4 min x mg/ml (median 4.2, range 2.4-8.4, SD 1.2 min x mg/ml). Statistical analysis revealed that the model was slightly biased (MPE%, 6.5%), but imprecise (RMSE%, 20.6%) in our study population. CONCLUSION: Although easy and attractive to use, the Ghazal-Aswad formula is not precise enough to predict the carboplatin AUC, and needs to be evaluated prospectively in other patient populations.

Adolescent↗

PubMed1999

A limited-sampling model for the pharmacokinetics of carboplatin administered in combination with paclitaxel.

PURPOSE: Carboplatin doses are often determined by using modified Calvert formulas. It has been observed that the area under the concentration versus time curve (AUC) for free carboplatin is lower than expected when modified formulas are used for carboplatin/paclitaxel chemotherapy combination regimens. By using limited-sampling models, the carboplatin AUC actually reached can easily be verified, and the dose adjusted accordingly. METHODS: In this report, we describe the development and validation of a limited-sampling model for carboplatin from 77 pharmacokinetic curves, when carboplatin is used in combination with paclitaxel. RESULTS: The following single-point model was selected as optimal: AUC carboplatin (min mg(-1) ml(-1)) = 418. c(2.5 h)(mg/ml) + 0.43 (min mg(-1) ml(-1)), where c(2.5 h) is the concentration (mg/ml) of carboplatin 2.5 h after the start of a 30-min infusion. This model proved to be unbiased (mean prediction error = 3.4 +/- 1.6%) and precise (root mean square error = 10.1 +/- 1.5%). CONCLUSIONS: The proposed model can be very useful for ongoing and future carboplatin/paclitaxel studies aimed to optimise and individualize treatment.

Aged↗

PubMed1999

Topoisomerase I/II inhibitor intoplicine administered as a 24 h infusion: phase I and pharmacologic study.

Intoplicine, an antitumor drug which interacts with both topoisomerase enzymes I and II, has demonstrated a broad spectrum of activity in preclinical studies. This indicates further clinical evaluation. In the present phase I study, with the primary objective to determine the maximum tolerated dose, intoplicine was administered by a 24 h continuous infusion every 21 days to 32 patients with solid malignant tumors. The patients received 12-640 mg/m2 by a central venous catheter. Liver toxicity was dose limiting. One patient died in a hepatic coma after the first course (dose 640 mg/m2), which was associated with intoplicine treatment. Other side effects were sporadic and mild. Myelotoxicity was virtually absent. Twenty-two patients had stable disease for four to six courses of treatment. The plasma concentration-time curves were compatible with standard linear pharmacokinetic models, with a protracted terminal half-life (mean 115 h). Although one sudden death occurred probably due to intoplicine toxicity, we nevertheless feel that research with intoplicine should continue, mainly because of its preclinical activity and its unique mechanism of action. The recommended dose for phase II studies with intoplicine administered as a 24 h infusion is 384 mg/m2. Liver toxicity, also seen in studies employing other dosages and infusion durations, should be investigated extensively in further clinical studies.

Adult↗

PubMed1998

Pharmacologic study of 3-hour 135 mg M-2 paclitaxel in platinum pretreated patients with advanced ovarian cancer.

Paclitaxel (Taxol(R)) is an active agent in platinum-refractory ovarian cancer. Since the available pharmacokinetic data of 135 mg m-2 paclitaxel administered by 3-h infusion are scarce and fragmented, we now describe a comprehensive pharmacologic study in a group of 13 patients who were pretreated with platinum for advanced ovarian cancer. The mean paclitaxel AUC was 10.3+/-2.4 h micromol l-1 (range 6.8-13.9 h micromol l-1). Quantification of the two major paclitaxel metabolites, 6alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel yielded AUCs of 0.44+/-0.30 h micromol l-1 and 0.31+/-0.20 h micromol l-1, respectively. The AUC of 3'-p-hydroxypaclitaxel was significantly different from that of patients with an altered hepatic function. The administration of 135 mg m-2 single-paclitaxel was safe, and the toxicities observed at higher doses in earlier studies were absent in this study. This is important, because the schedule and paclitaxel dose of 135 mg m-2 given by a 3-h infusion is expected to be used more frequently in combination with other cytotoxic agents with the aim of improving efficacy.

Adult↗

PubMed1997

Tailor-made chemotherapy for cancer patients.

Dosages of anticancer agents are usually calculated from a uniform standard-the body surface area (BSA). Although the BSA is proportionate to many physiological functions, it is however only partially related to the overall drug clearance. Consequently, a wide variability in drug exposure and drug concentrations can be found between patients, by which some experience little toxicity, while others may show severe toxic symptoms. It seems clear that monitoring of plasma drug concentrations can be a useful tool to further optimize current cancer chemotherapy. The problem that pharmacokinetic parameters are usually generated from concentration-time profiles obtained after multiple venepunctures can be reduced by applying limited sampling models (LSM). Other tailor-made dosing strategies include the Calvert formula for carboplatin dosing and strategies based on the characteristics of the individual patient. It can be concluded that the determination of pharmacokinetic parameters and adjustment of the drug dose in each patient to a predefined 'target' value with an optimal therapeutic outcome, could contribute substantially to improvement of current chemotherapeutic treatment.

Antineoplastic Agents↗

PubMed1997

Phase II study of the combination carboplatin and paclitaxel in patients with ovarian cancer.

BACKGROUND: Recently the feasibility of combining carboplatin with paclitaxel has been demonstrated in dose-finding studies. Maximum tolerated doses were 550 mg/m2 and 200 mg/m2 (three hours), respectively. We report now a phase II study in ovarian cancer patients. PATIENTS AND METHODS: Twenty-one chemo-naïve patients with optimally (n = 6) or suboptimally (n = 15) debulked stage III or IV ovarian cancer were treated every three weeks for six courses with paclitaxel (200 mg/m2) as a three-hour infusion, immediately followed by carboplatin (550 mg/m2) as a 30-minute infusion. RESULTS: Uncomplicated neutropenia was the principal toxicity, with mild anemia occurring regularly. As observed in the preceding phase I study, a relative lack of thrombocytopenia, generally grade III was found. Other toxicities consisted of mild neurotoxicity, nausea and vomiting, alopecia, myalgia, and bone pain. All suboptimally debulked patients responded to therapy. Overall, 12 patients underwent second-look laparoscopy, which revealed a pathologically confirmed complete remission in six. The median follow-up interval at the time of analysis was 14 months. Twelve patients are currently free of progression, at 8+ to 19 +/- months after the start of therapy. CONCLUSION: The carboplatin/paclitaxel combination appears to be a well-tolerated regimen, yielding high response rates. This combination has now gone forward to be evaluated in prospective randomized trials versus the cisplatin/paclitaxel combination.

Adult↗

PubMed1997

Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre.

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of paclitaxel (P) and carboplatin (C) in a sequence-finding and dose-escalating study in untreated non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Fifty-five chemotherapy-naive patients with NSCLC were entered onto the pharmacokinetic part of a large phase I trial in which P was administered as a 3-hour infusion at dosages of 100 to 250 mg/m2, and C over 30 minutes at dosages of 300 to 400 mg/m2. Patients were randomized for the sequence of administration, first C followed by P or vice versa. Each patient received the alternate sequence during the second and subsequent courses. RESULTS: The most important hematologic toxicity encountered-was neutropenia. Hematologic toxicity was not dependent on the sequence in which P and C were administered, but there was cumulative neutropenia. Nonhematologic toxicities consisted mainly of vomiting, myalgia, and arthralgia. No sequence-dependent pharmacokinetic interactions for the P area under the concentration-time curve (P-AUC), maximal plasma concentration (P-Cmax), or time above a threshold concentration of 0.1 mumol/L (P-T > or = 0.1 mumol/L) were observed. However, there was a significant difference for the metabolite 6 alpha-hydroxypaclitaxel AUC (6OHP-AUC). Higher 6OHP-AUCs were observed when C was administered before P. The mean plasma ultrafiltrate AUC of C (CpUF-AUC) at the dosage of 300 mg/m2 for the sequence C-->P was 3.52 mg/mL.min (range, 1.94 to 5.83) and 3.62 mg/mL.min for the sequence P-->C (range, 1.91 to 5.01), which is not significantly different (P = .55). Of 45 assessable patients, there were five major responders (three complete responders and two partial responders). Four of five responses occurred at dosages above dose level 4 (P 175 mg/m2 + C 300 mg/m2). The median survival duration was best correlated with the P dose (4.8 months for doses < 175 mg/m2 v 7.9 months for doses > or = 175 mg/m2, P = .07; P-T > or = 0.1 mumol/L, 4.8 months for < 15 hours v 8.2 months for > or = 15 hours, P = .06). CONCLUSION: There was no pharmacokinetic-sequence interaction between C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic parameter P-T > or = 0.1 mumol/L was related to improved survival in this study.

Adult↗

PubMed1997

Phase I and pharmacologic study of the combination paclitaxel and carboplatin as first-line chemotherapy in stage III and IV ovarian cancer.

PURPOSE: To determine the maximum-tolerated dose for the combination paclitaxel and carboplatin administered every 4 weeks and to gain more insight into the pharmacokinetics and pharmacodynamics of this combination in previously untreated ovarian cancer patients. PATIENTS AND METHODS: Thirty-five chemotherapy-naive patients with suboptimally debulked stage III (tumor masses > 3 cm) and stage IV ovarian cancer were entered onto this phase I trial in which paclitaxel was administered as a 3-hour intravenous (IV) infusion at dosages of 125 to 225 mg/m2 immediately followed by carboplatin over 30 minutes at dosages of 300 to 600 mg/m2. A total of six courses was planned, followed by a second-look laparoscopy/laparotomy. Patients with a response and/or minimal residual disease at second-look laparoscopy received three additional courses. Twenty-six patients participated in the pharmacokinetic part of the study. RESULTS: The most important hematologic toxicity encountered was neutropenia. Neutropenia was more pronounced for the higher dose levels (DLs) and was cumulative. Thrombocytopenia was mild in the first eight DLs, but increased during the treatment courses. Nonhematologic toxicities consisted mainly of vomiting, neuropathy, fatigue, rash, pruritus, myalgia, and arthralgia. Dose-limiting toxicities (DLTs) in this trial were neutropenic fever, thrombocytopenia that required platelet transfusions, and cumulative neuropathy. Of 33 patients assessable for response, 26 major responders (78%, 20 complete response [CR] and six partial response [PR]) were documented. The maximal concentration (Cmax) of paclitaxel and the area under the concentration-time curve (AUC) were not different from the historical data for paclitaxel as a single agent. Retrospective analysis using a modified Calvert formula showed that the measured carboplatin AUCs in plasma ultrafiltrate (pUF) were 30% +/- 3.4% less than the calculated carboplatin AUC. Neutropenia was more pronounced than could be expected on the basis of the historical times above a threshold concentration greater than 0.1 mumol/L (T > or = 0.1 mumol/L) or 0.05 mumol/L (T > or = 0.05 mumol/L), and thrombocytopenia was less than could be expected from historical sigmoidal Emax models. CONCLUSION: The combination of paclitaxel 200 mg/ m2 and carboplatin 550 mg/m2 every 4 weeks is a well-tolerated treatment modality. The paclitaxel-carboplatin combination is highly active in stage III (bulky) and stage IV ovarian cancer. No indications for a pharmacokinetic drug-drug interaction between carboplatin and paclitaxel were found.

Adult↗

PubMed1997

Clinical pharmacology of carboplatin administered in combination with paclitaxel.

The clinical pharmacology of carboplatin (C) administered with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (P) was investigated in two phase I studies undertaken in 83 previously untreated patients with either non-small cell lung cancer or ovarian cancer. Carboplatin was administered over 30 minutes and paclitaxel over 3 hours. Both agents were given every 4 weeks. Non-small cell lung cancer patients were randomized to two administration sequences, either carboplatin followed by paclitaxel (C-->P) or the reverse (P-->C). Each patient received the alternate sequence during the second and subsequent courses. Ovarian cancer patients uniformly received paclitaxel before carboplatin. Platinum concentrations in plasma ultrafiltrate were measured via flameless atomic absorption spectrometry, and 122 concentration-time curves were obtained. For non-small cell lung cancer patients, the mean area under the concentration-time curve (AUC) per 300 mg/m2 carboplatin was 3.52 mg/mL x min (range, 1.94 to 5.83) for the sequence C-->P and 3.62 mg/mL x min (range, 1.91 to 5.01) for the sequence P-->C. No sequence-dependent effect was observed (P > .5). For ovarian cancer patients, the mean AUC per 300 mg/m2 carboplatin was 3.83 mg/mL x min (range, 2.72 to 6.10), showing no difference when compared with data derived from non-small cell lung cancer patients (P = .13). In addition, the carboplatin AUC was not influenced by increasing paclitaxel doses from 100 to 250 mg/m2. Neutropenia was the principal toxicity, and anemia was frequent. However, there was a striking lack of thrombocytopenia. Modeling of the relationship between the carboplatin AUC and the decrease in platelets revealed a 50% decrease in platelets at a carboplatin AUC (AUC50) of 6.3 mg/mL x min. This contrasts with historical data documenting a carboplatin AUC50 of 4.0 mg/mL x min. Our findings suggest that there is a considerable interaction of both drugs at the cellular level, with at least an additive effect of carboplatin on the main hematologic toxicity of paclitaxel (ie, neutropenia). There is also a protective effect exerted by paclitaxel on carboplatin-related toxicity (ie, thrombocytopenia). The clear protective effect of paclitaxel in this combination suggests that it is possible to reduce the dose interval to 3 weeks. Studies are in progress to test this hypothesis and to investigate the underlying pharmacologic interactions.

Adult↗

PubMed1997

An overview of the clinical pharmacology of topotecan.

Topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA), a topoisomerase I inhibitor, is a semisynthetic camptothecin that has been structurally modified for increased water solubility. The closed lactone ring predominates at acidic pH, but the reverse reaction of the parent into the metabolite predominates at physiologic pH. The pharmacokinetic profile of topotecan is usually characterized by a two-compartment model and is linear in the dose range of 0.5 to 3.5 mg/m2. Following intravenous administration for 5 days at doses of 0.5 to 1.5 mg/m2/d as a 30-minute infusion, topotecan has a volume of distribution of approximately 130 L. Mean plasma clearance for topotecan (total) was approximately 1,000 mL/min with a plasma half-life of 2 to 3 hours. Renal clearance is an important determinant of topotecan elimination, with approximately 30% of the dose excreted in the urine. In three phase I studies in which the schedule of five daily doses every 21 or 28 days was investigated, all found 1.5 mg/m2/d to be the maximum tolerated dose. Neutropenia (reversible and noncumulative over time) was the major dose-limiting toxicity; fevers and infections were infrequently reported. The magnitude of topotecan exposure was correlated to the observed myelosuppression.

Antineoplastic Agents↗

PubMed1996

Evaluation of formulas using the serum creatinine level to calculate the optimal dosage of carboplatin.

Carboplatin is a chemotherapeutic agent frequently used in the treatment of various malignancies. An individual dosing strategy has been recommended to yield the most optimal exposure, expressed as the area under the concentration-time curve (AUC). The formula developed by Calvert et al. (dose = target-AUC x [GFR + 25]) can be used to achieve this. However, due to the inconvenient [51Cr]-ethylenediamine-tetraacetic acid ([51Cr]-EDTA)-based measurement of the glomerular filtration rate (GFR), its application in the clinic has thus far been limited. Chatelut and co-workers have recently proposed a formula to estimate carboplatin clearance using the serum creatinine concentration. We retrospectively tested the Chatelut equation and the Calvert formula using either the creatinine clearance based on 24-h urine collection or the creatinine clearance based on the formula of Cockcroft and Gault. The latter equations were shown to predict the carboplatin clearance reasonably well, although systematic overprediction and underprediction occurred. However, the formula proposed by Chatelut and co-workers had no significant bias and was precise. It is proposed that this formula be used to calculate the optimal carboplatin dosage after prospective validation has been performed.

Adult↗

PubMed1996

Pharmacokinetics and pharmacodynamics of topotecan given on a daily-times-five schedule in phase II clinical trials using a limited-sampling procedure.

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. We performed a pharmacokinetics study as part of phase II clinical trials in patients with various types of solid tumors, giving topotecan at 1.5 mg/m2 per day by 30-min infusion for 5 consecutive days, with courses being repeated every 3 weeks. Previously validated limited-sampling models, using concentration measurements in samples obtained 2 h after infusion, were used to calculate the area under the plasma concentration-time curves (AUCs) for both chemical forms. Samples were obtained from a total of 36 patients over 136 treatment days. The mean AUC of the closed-ring form (AUC(closed)) was 8.74 (range 2.3-16.3 microM min per day, and the mean AUC of the ring-opened form (AUC(open)) was 11.5 (range 3.2-46.0) microM min per day (interpatient variability 34-61%). In each patient the AUC values achieved on the 1st day of administration were similar to and, thus, predictive for those achieved during the following days, with a day-to-day variation of 7.39% being recorded for the AUC(closed) and that of 12.6% for the AUC(open). There was no drug accumulation during the 5 consecutive treatment days of each cycle. However, despite the large interpatient pharmacokinetic variability, the importance of regular drug monitoring on this schedule can be questioned, as the pharmacodynamic variability was relatively small.

Aged↗

PubMed1996

Pharmacokinetics and pharmacodynamics of carboplatin administered in a high-dose combination regimen with thiotepa, cyclophosphamide and peripheral stem cell support.

The aim of this pharmacokinetic/pharmacodynamic study was to define the relationships of the carboplatin exposure with the toxicity in patients treated with high dose carboplatin (400 mg m-2 day-1), cyclophosphamide (1500 mg m-2 day-1) and thiotepa (120 mg m-2 day-1) for four consecutive days, followed by peripheral stem cell transplantation. Exposure to carboplatin was studied in 200 treatment days by measuring the area under the carboplatin plasma ultrafiltrate (pUF) concentration vs time curve (AUC). The AUC was obtained by using a previously validated limited sampling model. A total of 31 patients was studied who received one, two or three courses of this high-dose chemotherapy regimen. The unbound, plasma ultrafiltrate carboplatin was almost completely cleared from the body before each next treatment day in a course; the day-to-day AUC variation was 3.3%. The mean cumulative AUC over 4 days was 19.6 (range 14.1-27.2) mg ml-1 min-1. In 97 treatment days the carboplatin dose was calculated using the Calvert formula with the creatinine clearance as the measure for the glomerular filtration rate (GFR). For these courses, the inter-patient variability in pharmacokinetics was significantly reduced from 21% to 15% (P = 0.007) in comparison with the schemes where it was given as a fixed dose of 400 mg m-2. There were no relationships found between toxicity and the AUC of carboplatin, which may be due to the influence of overlapping toxicities of cyclophosphamide and thiotepa. However, the ototoxicity was strongly related to the cumulative carboplatin AUC. This toxicity was dose limiting for carboplatin in this schedule. It appeared that the carboplatin pharmacokinetics in these regimens were similar to those reported at conventional dosages. To reduce the inter-patient variation, the carboplatin dose can be calculated using the Calvert-formula with the creatinine clearance as the measure for the GFR.

Antineoplastic Agents↗

PubMed1995

Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks.

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. The open form predominates at physiological pH. We performed a pharmacokinetic study as part of a phase I study in patients with various types of solid tumors, where topotecan was administered in a 30-min infusion daily on 5 consecutive days every 3 weeks. The plasma kinetics of topotecan could be described best using an open two-compartment model with t1/2(alpha) and t1/2(beta) of 8.1 (range 0.3 to 40.7) min and 132 (range 49 to 286) min, respectively. The plasma concentration-time profiles of the metabolite, however, could be described using a one-compartment model with t1/2(formation) of 29.0 (range 5.6-99.5) min and t1/2 (elimination of 123.2 (range 32-265) min, respectively. The lactone was the predominate form during the first hour from the start of infusion, but was rapidly converted into its ring-opened structure. The elimination rate of topotecan was independent of the dose. There were linear relationships between the dose (mg m-2 day-1), the area under the plasma concentration versus time curve (AUC) of topotecan and its metabolite, the total AUC, peak plasma lactone concentrations, and the time period that the topotecan concentrations remained above 10 nM. Different models were used to correlate pharmacokinetic and pharmacodynamic parameters. The percentage decrease in absolute neutrophil count (ANC) was related to these parameters and plots were well fitted by linear and sigmoidal Emax models.

Adult↗

PubMed1995

The use of the Calvert formula to determine the optimal carboplatin dosage.

Carboplatin is a chemotherapeutic agent frequently used in the treatment of various malignancies. The myelotoxicity and clinical efficacy of carboplatin correlate with the clearance of the drug, which is correlated to the glomerular filtration rate (GFR). Dosing of this agent based solely upon the patients body surface area is therefore not accurate enough; the GFR, and thus the clearance of carboplatin differ in each patient irrespective of the body area. Consequently, some patients undergo a higher systemic exposure, expressed as the area under the plasma concentration/time curve (AUC), than others when dosages of carboplatin are given on the basis of the body surface area. A high AUC correlates with increased toxicity, thus increasing the risks of the treatment, but in the case of a low AUC the therapeutical efficacy decreases. This indicates that an individual dosing strategy is warranted to obtain the optimal AUC. In this article, the development and application of a simple equation, known as the Calvert formula, are discussed. This formula can be used to calculate the carboplatin dose accurately in order to obtain a target AUC by using only the GFR. The formula is: dose (mg) = AUC (mg ml-1 min) x [GFR (ml/min) + 25 (ml/min)]. This formula has proven to be, in both retrospective and prospective studies, a reliable tool to calculate the optimal dose of carboplatin Future studies should determine the value of the creatinine clearance as a measure for the GFR.

Carboplatin↗

PubMed1995

Monitoring carboplatin concentrations in saliva: a replacement for plasma ultrafiltrate measurements?

There is an increasing interest in using saliva as a biological matrix for drug monitoring, because it can be obtained by a noninvasive and patient-friendly means. In this article we describe our experience with respect to the practical use of saliva for pharmacokinetic monitoring of the anticancer agent carboplatin. Plasma ultrafiltrate (pUF), unstimulated, and citric acid-stimulated saliva samples were obtained from 17 patients receiving 175-350 mg/m2 carboplatin in different combination regimens. Platinum concentrations of carboplatin were determined by using a validated Zeeman atomic absorption spectrometric method. Carboplatin was detectable both in saliva and in pUF for at least 24 h after intravenous administration. Maximum concentrations in saliva ranged between 0.13 and 1.15 mg/L and were reached approximately 1.3 h (range 0-3.8 h) after the end of the infusion. The ratios of carboplatin levels in pUF and saliva were time dependent and patient dependent. The ratios of the clinically relevant carboplatin area under the concentration-time curve (AUC) in pUF and saliva varied between 11 and 150 (mean 45). Based on this large variation, we conclude that in this setup, saliva drug concentrations are not a reliable replacement for carboplatin analysis in pUF.

Adolescent↗

PubMed1995

Phase I clinical and pharmacokinetic study of topotecan administered by a 24-hour continuous infusion.

PURPOSE: To determine the maximum-tolerable dose (MTD) and to investigate the pharmacokinetics and pharmacodynamics of topotecan in a phase I study. Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. Broad preclinical activity rationalized further clinical evaluation. PATIENTS AND METHODS: In this phase I trial, topotecan was administered by 24-hour continuous infusion every 21 days to patients with solid malignant tumors. RESULTS: A total of 25 eligible patients, of whom 22 were pretreated, entered the study. They received the following dosages of topotecan: 2.5, 3.75, 5.60, 8.4, and 10.5 mg/m2 by 24-hour infusion. Reversible leukopenia and thrombocytopenia were dose-limiting, with mild anemia occurring regularly. Other toxicities, such as alopecia, mucositis, nausea, and vomiting were sporadic and mild. Responses were not observed. However, eight patients had stable disease. The plasma concentration-time curves were not compatible with standard linear pharmacokinetic models, and indications were found for the occurrence of nonlinear (saturation) kinetics at the dosages studied. CONCLUSION: The recommended dose for phase II studies is 8.4 mg/m2 when administered as a 24-hour infusion, which is well tolerated. Further studies will be necessary to account for the putative nonlinear behavior of the drug.

Adult↗