Concentration- or effect-controlled clinical trials with sparse data.
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Adult↗
Biomedical subjects
A Forrest
Publications and source records attributed to A Forrest.
Ticarcillin-clavulanic acid pharmacokinetics in preterm neonates with presumed sepsis.
The objective of the reported study was to characterize the pharmacokinetics of ticarcillin and clavulanic acid in premature low-birth-weight (less than 2,200 g) neonates with presumed sepsis. Eleven infants received 12 courses of ticarcillin-clavulanic acid at 75 mg/kg of body weight intravenously every 12 h. Blood samples were collected at 0.5, 1.5, 4, and 8 h following the infusion of the initial dose. The concentrations of ticarcillin and clavulanic acid were determined by a microbiologic assay. Median (interpatient coefficients of variation) values for the volume of the central compartment, total steady-state volume, distributional clearance, total clearance, and terminal elimination half-life for ticarcillin were 0.030 liter/kg (21%), 0.26 liter/kg (48%), 0.41 liter/h/kg (47%), 0.047 liter/h/kg (47%), and 4.2 h (45%), respectively. For clavulanic acid the parameters were 0.28 liter/kg (32%), 0.36 liter/kg (34%), 11 liters/h/kg (36%), 0.12 liters/h/kg (72%), and 1.95 h (40%), respectively. Our results suggest that the current dosing recommendations of 75 mg/kg every 12 h risk subtherapeutic clavulanic acid concentrations and that 50 mg/kg every 6 h is a more rational dosing strategy.
Anti-Bacterial Agents↗
Pharmacokinetics and bioavailability of fluconazole in patients with AIDS.
Fluconazole pharmacokinetics were evaluated for 10 volunteers with AIDS who had no clinical evidence of gastroenteritis. Single 100-mg intravenous (i.v.) and oral (p.o.) doses were administered in a randomized, crossover design. i.v. doses were delivered by a constant-rate infusion over 30 min. Serum fluconazole concentrations were measured by gas-liquid chromatography. The i.v. and p.o. studies were modelled simultaneously by iterative two-stage analysis, which provided individual parameter estimates and a population pharmacokinetic model. Median areas under the concentration-time curves for i.v. and p.o. studies did not differ (90.6 and 99.3 micrograms/ml.h, respectively). Consistent with this finding, the median fractional bioavailability was 1.1 (range, 0.45 to 1.3), comparable to those in healthy subjects. Serum pharmacokinetics in these AIDS patients were generally similar to published data for healthy volunteers. However, following p.o. dosing, we observed a slightly delayed and highly variable time to maximum concentration in serum (median, 2 h; range, 15 min to 8 h). Data were well described by a linear, two-compartment pharmacokinetic model with first-order absorption and elimination. Repeated-measures analysis of variance found no significant differences among any of the pharmacokinetic parameters between i.v. and p.o. studies. On the basis of our findings, we suggest no change in dosage of p.o. fluconazole in patients with AIDS who show no clinical signs of enteropathy.
Acquired Immunodeficiency Syndrome↗
Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin.
Data obtained from 74 acutely ill patients treated in two clinical efficacy trials were used to develop a population model of the pharmacokinetics of intravenous (i.v.) ciprofloxacin. Dosage regimens ranged between 200 mg every 12 h and 400 mg every 8 h. Plasma samples (2 to 19 per patient; mean +/- standard deviation = 7 +/- 5) were obtained and assayed (by high-performance liquid chromatography) for ciprofloxacin. These data and patient covariates were modelled by iterative two-stage analysis, an approach which generates pharmacokinetic parameter values for both the population and each individual patient. The final model was used to implement a maximum a posteriori-Bayesian pharmacokinetic parameter value estimator. Optimal sampling theory was used to determine the best (maximally informative) two-, three-, four-, five-, and six-sample study designs (e.g., optimal sampling strategy 2 [OSS2] was the two-sample strategy) for identifying a patient's pharmacokinetic parameter values. These OSSs and the population model were evaluated by selecting the relatively rich data sets, those with 7 to 10 samples obtained in a single dose interval (n = 29), and comparing the parameter estimates (obtained by the maximum a posteriori-Bayesian estimator) based on each of the OSSs with those obtained by fitting all of the available data from each patient. Distributional clearance and apparent volumes were significantly related to body size (e.g., weight in kilograms or body surface area in meters squared); plasma clearance (CLT in liters per hour) was related to body size and renal function (creatinine clearance [CLCR] in milliliters per minute per 1.73 m2) by the equation CLT = (0.00145.CLCR + 0.167).weight. However, only 30% of the variance in CLT was explained by this relationship, and no other patient covariates were significant. Compared with previously published data, this target population had smaller distribution volumes (by 30%; P < 0.01) and CLT (by 44%; P < 0.001) than weight- and CLCR- matched stable volunteers. OSSs provided parameter estimates that showed good to excellent estimates of CLT (or area under the concentrations-time curve [AUC]) were unbiased and precise (e.g., r2 for AUC for all data versus AUC for OSS2 was > 0.99) and concentration-time profiles were accurately reconstructed. These results will be used to model the pharmacodynamic relationships between ciprofloxacin exposure and response and to aid in developing algorithms for individual optimization of ciprofloxacin dosage regimens.
Adult↗
Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients.
Seventy-four acutely ill patients were treated with intravenous ciprofloxacin at dosages ranging between 200 mg every 12 h and 400 mg every 8 h. A population pharmacokinetic-pharmacodynamic analysis relating drug exposure (and other factors) to infectious outcome was performed. Plasma samples were obtained and assayed for ciprofloxacin by high-performance liquid chromatography. Samples from patients were frequently cultured so that the day of bacterial eradication could be determined. The pharmacokinetic data were fitted by iterative two-stage analysis, assuming a linear two-compartment model. Logistic regression was used to model ciprofloxacin exposure (and other potential covariates) versus the probabilities of achieving clinical and microbiologic cures. The same variables were also modelled versus the time to bacterial eradication by proportional hazards regression. The independent variables considered were dose, site of infection, infecting organism and the MIC for it, percent time above the MIC, peak, peak/MIC ratio, trough, trough/MIC ratio, 24-h area under the concentration-time curve (AUC), AUC/MIC ratio (AUIC), presence of other active antibacterial agents, and patient characteristics. The most important predictor for all three measures of ciprofloxacin pharmacodynamics was the AUIC. A 24-h AUIC of 125 SIT-1.h (inverse serum inhibitory titer integrated over time) was found to be a significant breakpoint for probabilities of both clinical and microbiologic cures. At an AUIC below 125 (19 patients), the percent probabilities of clinical and microbiologic cures were 42 and 26%, respectively. At an AUIC above 125 (45 patients), the probabilities were 80% (P < 0.005) and 82% (P < 0.001), respectively. There were two significant breakpoints in the time-to-bacterial-eradication data. At an AUIC below 125 (21 patients), the median time to eradication exceeded 32 days; at an AUIC of 125 to 250 (15 patients), time to eradication was 6.6 days: and at AUIC above 250 (28 patients), the median time to eradication was 1.9 days (groups differed; P < 0.005). These findings, when combined with pharmacokinetic data reported in the companion article, provide the rationale and tools needed for targeting the dosage of intravenous ciprofloxacin to individual patients' pharmacokinetics and their bacterial pathogens' susceptibilities. An a priori dosing algorithm (based on MIC, patient creatine clearance and weight, and the clinician-specified AUIC target) was developed. This approach was shown, retrospectively, to be more precise than current guidelines, and it can be used to achieve more rapid bacteriologic and clinical responses to ciprofloxacin, as a consequence of targeting the AUIC.
Adult↗
A preliminary trial of the gel test for blood group serology.
The gel test, first reported in 1988, can be used for most areas of blood group serology, but this report deals specifically with ABO/Rh typing and antibody screening and investigation. The technique is simple and quick to perform and the reading of results is standardised and clean with no false-positive reactions being found in antiglobulin tests. Since gel anti-human globulin tests require no washing and the test cards may be sealed during centrifugation, the system is particularly advantageous for 'loosely bound' antibodies and 'high-risk' samples.
Blood Grouping and Crossmatching↗
Use of adaptive control with feedback to individualize suramin dosing.
Suramin is the first putative growth factor inhibitor in clinical trial that has demonstrated antitumor activity. Administration of suramin is complicated by a narrow therapeutic index and significant interpatient variability of measured pharmacokinetic parameters. Because both antitumor response and dose-limiting toxicities are related to plasma suramin concentration profiles, individualized dose schedules are required for optimal administration of the compound. In this report, the use of optimal sampling theory to derive sparse data monitoring and control strategies for use with suramin is described. A fixed rate continuous infusion schedule was used in seven patients, and the time to peak concentration (280-300 micrograms/ml) ranged from 7.7-21 days (mean, 13.2 days) with a decline to 150 micrograms/ml in 3-22 days (mean, 11 days). An initial population pharmacokinetic model was fit using a maximum likelihood algorithm. The mean volume of the central compartment was 4.5 +/- 6.7 liters/m2, volume of the peripheral compartment 10.6 +/- 1.4 liters/m2, distributional half-life 25 +/- 5.4 h, and elimination half-life 29.7 +/- 6.9 h. The terminal half-life was shorter than previously reported. These parameters were used as the initial population model for an iterative 2-stage analysis. The resulting distributional half-life of 22.3 +/- 2.7 h and elimination half-life of 28.2 +/- 5.0 h were similar, reflecting the intensive sampling. The iterative 2-stage analysis model was then used to determine the optimal sampling times and to simulate 20 data sets for a protocol designed to maintain plasma concentrations in a defined concentration range. This strategy is currently under investigation in phase I clinical trials.
Adenocarcinoma↗
Approaches to optimal dosing of hexamethylene bisacetamide.
HMBA is a potent differentiating agent capable of causing > 95% morphological differentiation in cell lines in vitro. The induction of differentiation is dependent on both the concentration of and the duration of exposure to HMBA. However, acute toxicities (neurotoxicity and acidosis) have limited the maximal HMBA css value to < 2 mM, which is at the lower limit of effective in vitro concentrations. When HMBA css values have been maintained at 1-2 mM, thrombocytopenia has limited the duration of HMBA infusion to < or = 10 days. The present studies were performed to determine whether exposure to HMBA could be individualized and maximized without resulting in intolerable toxicity to patients and to determine which factors would predispose a patient to the development of acute toxicity during treatment with HMBA. For these investigations, patients were given HMBA at a target css using an adaptive-feedback-control method rather than at a set dose. Because HMBA administration produces large anion gaps, a simple maneuver such as alkalinization might enable the escalation of plasma HMBA css values to > 2 mM. HMBA was given as a 5-day CI to 14 patients (26 courses) at 2 target HMBA css levels near the maximal tolerated value in the presence or absence of concurrent alkalinization with sodium bicarbonate. Symptomatic acidosis occurred in one patient who did not receive bicarbonate. Neurotoxicity proved to be dose-limiting at the target HMBA css value of 1.5-2.0 mM in the absence of concurrent alkalinization and at a css level of > 2 mM, regardless of alkalinization. No neurotoxicity was seen at target HMBA css values of 1.5-2.0 mM in patients who did receive concurrent alkalinization. Alkalinization was not associated with any detectable changes in plasma HMBA metabolites. With the maximal tolerable 5-day HMBA css having thus been defined at 1.5-2.0 mM, we attempted to maximize exposure to HMBA by defining a tolerable duration of infusion. Individualization of the duration of HMBA infusion to a target nadir PLT was performed in patients who had received an initial 5-day CI of HMBA at a css 1.5-2.0 mM along with concurrent alkalinization. The AUC achieved and the thrombocytopenia produced during this first course were used to predict the duration of infusion that each patient would subsequently tolerate (at an HMBA css of 1-2 mM) to achieve a nadir PLT of 75,000-100,000/microliters.(ABSTRACT TRUNCATED AT 400 WORDS)
Acetamides↗
The significance of CD34 and TdT determinations in patients with untreated de novo acute myeloid leukemia.
The results of intensive chemotherapy given to 247 adults at the University of Maryland Cancer Center with previously untreated de novo acute myeloid leukemia (AML) were reviewed with respect to expression of terminal deoxynucleotidyl transferase (TdT) and CD34. Of the 228 patients with data for TdT, 32 (14%) had > 5% of the leukemia cells positive by an immunofluorescence assay. The median age of the TdT-positive patients was approximately 10 years less than the TdT-negative patients (50 versus 60 years). Patients with TdT-positive AML had similar median survival (12 versus 10.5 months) and complete remission (CR) rates (53 versus 59%), but a greater frequency of long-term complete responders (60 of complete remitters versus 20%, p = 0.08) than TdT-negative patients. Of 126 patients tested, 59% were CD34-negative (< 20% reactivity with leukemia cells). These 74 patients (median age 60 years) had a greater CR rate (71 versus 48%, p = 0.008) than the 52 CD34-positive patients (median age 60 years), and improved survival (p = 0.013 by Wilcoxon) although there was no difference in the duration of CR between the CD34-positive and negative groups. Of CD34-positive patients 12/52 remain in continuous CR, and 16/74 CD34-negative patients remain in continuous CR. None of eight patients strongly positive for CD34 (> 70% reactivity) remain disease-free. Positivity for TdT or CD34 was associated with less differentiated AML. Of CD34-positive patients, 44% had FAB M0/M1 morphology versus 13% of CD34-negative patients (p = 0.0001); similarly, 47% of TdT-positive patients were FAB M0/ML1 versus 25% of TdT-negative patients (p = 0.01). Of seven patients with FAB M4E0, five were CD34-positive. Of the 12 CD34-positive survivors, four had FAB M4E0. Thus CD34 expression predicts for CR rate and overall survival in adults with AML. TdT expression does not significantly affect overall outcome but may be associated with longer CR durations.
Acute Disease↗
Use of plasma cytotoxic activity to model cytotoxic pharmacodynamics of anticancer drugs.
We have developed a pharmacokinetic/pharmacodynamic approach that integrates the disposition, cytotoxic activity and interaction of anticancer drugs. Fundamental to this approach is the measurement of the cytotoxicity, against a "target" cell line, of patient plasma collected at different times after administration of the anticancer agent(s). To illustrate this approach, we have studied the plasma cytotoxic activity (PCA), against HL-60 cells, of plasma from 11 acute myeloblastic leukemic patients treated with daunorubicin (DNR). Plasma, obtained before and serially for 24 h after DNR treatment, was assayed by HPLC for DNR and daunorubicinol (DNRol), its active metabolite. The corresponding observed PCA values (PCAobs) against HL-60 cells were also measured with a flow-cytometric cell-survival assay that we had developed previously. The pharmacodynamics, i.e. PCA, were co-modeled (dual Hill equation with an interaction term to allow synergism or antagonism) with the pharmacokinetics. The integration of the PCA profile provided the area under the observed PCA versus time curve (AUCobs). For each patient, we also generated an "interaction panel", by adding known amounts of DNR and DNRol to his or her pretreatment plasma. The corresponding cytotoxicities were measured, and then applied to the pharmacodynamic model. This provided a standard surface from which the PCA of each sample obtained after therapy was predicted (PCAprd), on the basis of assayed concentrations of DNR and DNRol in that sample. For plasma samples obtained after treatment, the model simultaneously fit all three outputs, i.e. PCA and DNR/DNRol concentration, very well. We observed substantial interpatient variability in HL-60 growth rate in medium containing patient pretreatment plasma, in DNR activity in pretreatment plasma, and in the in vitro activity (PCA) of plasma obtained after DNR treatment. We also compared the AUCprd to the AUCobs for each patient, and we identified a subset of 4/11 acute myeloblastic leukemic patients who had developed much more PCA after DNR administration that could be explained by the measured concentrations of DNR and DNRol. This may be due to unidentified active metabolites or to factors produced in the plasma in response to the treatment. This pharmacokinetic/pharmacodynamic model is promising to describe pharmacodynamics and interactions of anticancer drugs in cancer patients.
Adult↗
Phase I clinical and pharmacokinetic study of zeniplatin, a new platinum complex.
Forty-six patients with refractory solid malignancies received the new platinum complex [2,2-bis(aminomethyl)-1,3-propanediol-N-N'] [1,1-cyclobutanedicarboxylato] [(2-)0,0')] platinum (zeniplatin). Zeniplatin was given, without hydration or mannitol, as a 60- to 90-min i.v. infusion every 3 weeks at doses ranging from 8 to 145 mg/m2. The maximum tolerated dose of zeniplatin was 145 mg/m2. The dose-limiting toxicity of zeniplatin was dose-related leukopenia and neutropenia, with the nadir usually observed between 1 and 2 weeks after therapy and recovery usually occurring by 3 weeks after therapy. Thrombocytopenia was rare. The most prominent non-hematological side-effect of zeniplatin was nausea and vomiting. Other non-hematological side-effects were mild or absent. Zeniplatin did not induce significant neurological or auditory toxicity. Zeniplatin was not nephrotoxic at doses less than or equal to 120 mg/m2. At 145 mg/m2, the clearance decreased by a mean of 40% after 2 cycles of therapy. Two patients, one with malignant melanoma and one with renal cell cancer, achieved a partial response. Pharmacokinetics of free (plasma ultrafiltrates) and total platinum in plasma were determined in 5 patients. An in vitro study of the rate and extent of zeniplatin binding to protein in human plasma was also performed. Free and total platinum were measured by flameless atomic absorption spectrometry; free zeniplatin was measured in ultrafiltrate by HPLC. Total and free plasma platinum concentrations were co-modelled using the information from the in vitro study.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole.
During a phase I trial of 3-day simultaneous continuous intravenous infusions of varying doses of fluorouracil (5FUra) and 7.7 mg/kg/d of dipyridamole, we examined the relationships between 5FUra dose and steady-state plasma concentration (Css) and the percentage reduction in WBCs, as well as the percentage frequency of stomatitis. The 5FUra was administered at doses ranging from 185 mg/m2/d times three to 3,600 mg/m2/d times three. In 42 patients, 86 cycles of 5FUra plus dipyridamole and 28 cycles of 5FUra alone were analyzed. The Css of 5FUra varied even within the same dose level. When patients receiving the same 5FUra dose were considered, the interpatient coefficient of variation of 5FUra Css in cycles of 5FUra plus dipyridamole was 23% +/- 4.2%. For courses of 5FUra alone, the coefficient of variation of 5FUra was 15.6% +/- 6.5%. When the occurrence of any degree of stomatitis was related to the Css 5FUra, with patients grouped in cohorts of 2-mumol/L increments, the following equations accurately described the frequency of stomatitis: for 5FUra plus dipyridamole, percentage frequency of stomatitis = 100(1-e-0.114Css), r2 = 0.88; for 5FUra alone, percentage frequency stomatitis = 100(1-e0.122Css), r2 = 0.80. When 5FUra dose was substituted for Css, these relationships were as follows: percentage frequency of stomatitis = 100(1-e-0.00031 [dose]), r2 = 0.85; and percentage frequency of stomatitis = 100(1-e-0.00051 [dose]), r2 = 0.80. When the relationship between the percentage reduction in WBC and Css 5FUra was examined, statistically significant relationships were also apparent: for 5FUra plus dipyridamole, percentage reduction in WBC = 100(1-e-0.085Css), r2 = 0.46; for 5FUra alone, percentage reduction in WBC = 100(1-e-0.060Css), r2 = 0.61. When 5FUra dose was substituted for Css, these relatinships were as follows: percentage reduction in WBC = 100(1-e-0.00023 [dose]), r2 = 0.40; percentage reduction in WBC = 100(1-e-0.00024 [dose]), r2 = 0.65. The relationship between either Css 5FUra or dose 5FUra and either stomatitis or myelosuppression were also well described by the modified Hill equation (J Theor Biol 20:171-201, 1968). These analyses indicate that it should be possible to develop therapeutic regimens wherein 5FUra is administered to achieve a targeted Css determined by the risk and severity of toxicity deemed acceptable.
Bone Marrow Diseases↗
Multiple-dose activate charcoal as adjunct therapy after chronic phenytoin intoxication.
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Aged↗
Effect of renal function on the bioavailability of ciprofloxacin.
The effect of renal function on the bioavailability of ciprofloxacin was studied in 21 subjects with measured creatinine clearances ranging from 0 to 8.99 liters/h per 1.73 m2. Each subject received ciprofloxacin, 200 mg intravenously and 750 mg orally, separated by at least 1 week. Serial (12 to 15) blood samples were obtained over 24 to 48 h. Concentrations in serum were assayed by high-pressure liquid chromatography. Area under the curve was calculated by the trapezoidal rule with extrapolation to infinity. Bioavailability was calculated as the ratio between the dose-normalized area under the curve of oral and intravenous administrations. The overall mean (standard deviation) bioavailability observed was 63.4% (14.6%), similar to that observed in those with normal renal function (69.0% [15.7%]). The mean bioavailability in the subgroup of subjects with renal insufficiency was 59.9% (13.3%). The observed range in bioavailability was 33.9 to 91.4%. Linear regression did not reveal a correlation between creatinine clearance and bioavailability. Renal insufficiency does not appear to affect ciprofloxacin bioavailability.
Administration, Oral↗
Appetite stimulation and weight gain with megestrol acetate.
The extreme anorexia and cachexia associated with cancer and other disease states often have important physical and psychologic impact on both patients and their families. Weight gain resulting from megestrol acetate therapy in breast cancer patients suggests that progestins may be useful for alleviation of disease-associated appetite and weight loss. Early breast cancer experience, as well as preliminary data from a randomized, placebo-controlled trial of high-dose megestrol acetate in cancer anorexia and wasting, is therefore reviewed. Although the precise mechanism by which megestrol acetate exerts its effect remains unclear, weight gain was observed in 75% of patients in the high-dose study and in nearly all of those who remained on therapy for 6 weeks. It was concluded that, although megestrol acetate cannot be expected to directly affect the prognosis of patients with hormone-insensitive tumors, it may increase host resistance by improving nutritional status and/or enhancing the quality of life.
Adult↗
Ciprofloxacin pharmacokinetics in critically ill trauma patients.
The steady-state pharmacokinetics of ciprofloxacin 200 mg intravenously every 12 hours was examined in 10 critically ill trauma patients. The mean parameter estimates for total clearance, renal clearance, non-renal clearance, and volume of distribution were 30.08 liters/hour/1.73 m2, 16.62 liters/hour/1.73 m2, 13.46 liters/hour/1.73 m2, and 2.10 liters/kg. Although the mean values were similar to those previously reported, significant individual differences were observed, with the coefficient of variation ranging from 41 to 61 percent. Non-renal clearance appeared to have a bimodal distribution. The dosage studied appeared to provide adequate serum concentration profiles to treat most pathogens found in infected trauma patients. However, the use of higher doses and more frequent dosing may be required to treat patients with Staphylococcus aureus and Pseudomonas aeruginosa infections.
Adult↗
Phase I trial using adaptive control dosing of hexamethylene bisacetamide (NSC 95580).
Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was administered to patients with refractory malignant tumors. Thirteen patients received 30 evaluable courses. HMBA was given by continuous i.v. infusion for 5 days. Therapy was repeated every 28 days, if patients had recovered from toxicity. The starting dose was 24 g/m2/day. Because our previous trial had shown wide interpatient variability in HMBA pharmacokinetics and excess toxicity at HMBA plasma concentrations greater than 2 mM (HMBA doses between 24 and 33.6 g/m2/day), we attempted to individualize each patient's dose based on a dosing scheme using an adaptive (feedback) control algorithm, which assumed linear clearance for HMBA. In all courses, a plasma sample was assayed daily and infusion rates were adjusted to achieve an HMBA plasma concentration of 1.5-2.0 mM (300-400 mg/liter). The patients included 12 men and 1 woman with a median age of 56 years (range, 34-76) and median Karnofsky performance status of 90% (range, 60-100). All patients had received prior chemotherapy and 9 patients had also received radiation therapy. The linear adaptive control algorithm was reasonably precise, with a mean absolute error of 0.28 (SE 0.04) mM. However, adjustments in infusion rate systematically overshot the desired change in steady state concentration, probably due to nonlinear clearance of HMBA. For levels within 24 h of a change in infusion rate, this resulted in significant bias, with a mean error of 0.24 (SE 0.09) mM. The mean absolute error was 0.40 (SE 0.06) mM. A second adaptive control algorithm, using a pharmacokinetic model with parallel first-order (renal) clearance and Michaelis-Menten (nonrenal) clearance and using Bayesian parameter estimation with a priori estimates based on our previous phase I trial, proved to be much more precise than the linear method and was unbiased when applied retrospectively to the same observations, with a mean error (within 24 h of a change in infusion rate) of 0.02 (SE 0.06) mM and a mean absolute error of 0.22 (SE 0.03) mM. Toxicity was reversible in all cases. Neurotoxicity, consisting of hallucinations, agitation, somnolence, or confusion, was seen in 2 patients. Four patients complained of insomnia or anxiety. Mild asymptomatic acidosis was seen in 3 patients. Other toxicity included grade 1-2 nausea and vomiting (10 patients), grade 2 diarrhea (2 patients), grade 3 thrombocytopenia (3 patients), grade 1-3 leukopenia (3 patients), and oral herpes simplex infection (4 patients). Mild reversible renal insufficiency (measured by creatinine clearance) was seen in 8 patients.(ABSTRACT TRUNCATED AT 400 WORDS)
Acetamides↗
A limited sampling strategy for cyclophosphamide pharmacokinetics.
A limited sampling strategy was developed to estimate the total area under the curve of plasma cyclophosphamide concentrations versus time (AUC). The strategy was developed with a training set consisting of 29 pharmacokinetic studies in 16 patients who received 1-h i.v. infusions of cyclophosphamide at a dosage of 1000 mg/m2. The strategy was developed by applying stepwise forward multiple regression analysis to cyclophosphamide concentrations observed at each time in the training set (independent variables) versus the AUC (dependent variable). It was confirmed by applying stepwise backward elimination regression analysis to the same data set. The final sampling strategy, which utilized three time points, was: AUC = 40.18C24 + 8.79C4 + 0.83C1 - 28 (dosage/1000), where C24, C4, and C1 represent plasma cyclophosphamide concentrations at 24, 4, and 1 h, respectively, and the dosage is in mg/m2 (r = 0.98). The strategy was validated prospectively with a test data set consisting of 14 pharmacokinetic studies in 11 patients who received 1-h i.v. infusions of cyclophosphamide at dosages of 300, 600, or 1200 mg/m2. The strategy proved highly predictive, with correlation coefficient between predicted and actual AUC of 0.94. The strategy also proved unbiased, with mean percentage of error (+/- SE) of 3.3 +/- 3.6%, and precise, with mean absolute percentage of error of 9.3 +/- 2.7%. The sampling strategy developed is being used in a multiinstitution trial of cyclophosphamide in an effort to relate cyclophosphamide pharmacokinetics, as expressed by AUC, with the toxic or therapeutic pharmacodynamic responses of the drug.
Cyclophosphamide↗