Is mixed effects modeling or naïve pooled data analysis preferred for the interpretation of single sample per subject toxicokinetic data?

The purpose of this study was to evaluate whether mixed effects modeling (MEM) performs better than either noncompartmental or compartmental naïve pooled data (NPD) analysis for the interpretation of single sample per subject pharmacokinetic (PK) data. Using PK parameters determined during a toxicokinetic study in rats, we simulated data sets that might emerge from similar experiments. Data sets were simulated with varying numbers of animals at each sampling time (4-48) and the number of samples taken (1-3) from each individual. Each data set was replicated 50 times and analyzed using several variations of MEM that differed in the assumptions made regarding intraindividual error, NPD, and a graphical noncompartmental method. These analyses attempted to retrieve the underlying parameter and covariate effect values. We compared these analysis methods with respect to how well the underlying values were retrieved. All analysis methods performed poorly with single sample per subject data but MEM gave less biased estimates under the simulated conditions used here. MEM performance increased when covariate effects were sought in the analysis compared with analyses seeking only PK parameters. Decreasing the number of animals used per sampling time from 48 to 16 did not influence the quality of parameter estimates but further reductions (< 16 animals per sampling time) resulted in a reduced proportion of acceptable estimates. Parameter estimate quality improved and worsened with MEM and NPD, respectively, when additional samples were obtained from each individual. Assumptions made regarding the magnitude of intraindividual error were unimportant with single sample per subject data but influenced parameter estimates if more samples were obtained from each individual. MEM is preferable to both NPD and noncompartmental approaches for the analysis of single sample per subject data but even with MEM estimates of clearance are often biased.

Analysis of toxicokinetic data using NONMEM: impact of quantification limit and replacement strategies for censored data.

The purpose of this study was to examine how best to incorporate plasma samples which fall below an assay's lower limit of quantification into the process of toxicokinetic data modeling. Secondly to establish what proportion of data can be below the quantification limit without compromising NONMEM's parameter estimates. Using pharmacokinetic parameters determined in a rat toxicokinetic study we simulated datasets that might emerge from similar experiments in which only one sample was obtained per individual. A number of quantification limits were used which resulted in increasing proportions of data values being treated as if they were below the limit of quantification (BQL). For each quantification level we incorporated BQL data into our analyses in number of ways. We compared these analysis methods with respect to how well the underlying parameter values were retrieved. Omitting BQL data values or entering them as zero led to inaccurate and biased study results. We found that incorporating BQL values using more complex substitution methods via a mixed effects model produced more reliable and less biased parameter estimates. The four substitution methods that we investigated performed similarly. Parameter estimates became less reliable and more biased as the quantification level was increased depending on the method of BQL value incorporation. Naive methods of BQL data handling can produce unreliable and biased parameter estimates. An alternative is to incorporate BQL values into a population-type model, our results showed this method to be preferable. We found it advisable that the proportion of BQL data should not exceed one third and, if possible should be less than one quarter.

Validation of a highly sensitive ICP-MS method for the determination of platinum in biofluids: application to clinical pharmacokinetic studies with oxaliplatin.

ELOXATIN (Oxaliplatin) is a novel platinum containing anti-cancer agent with a diaminocyclohexane carrier ligand which has been approved in several major European countries. Clinical studies have demonstrated that the compound exhibits marked activity against colorectal cancers in combination with 5-fluorouracil (5-FU). The aim of this work was to develop and validate a highly sensitive inductively coupled plasma mass spectrometry assay for the determination of oxaliplatin-derived platinum in plasma ultrafiltrate, plasma and whole blood and to apply this technique to clinical pharmacokinetic studies with oxaliplatin. Ultratrace detection of platinum in plasma ultrafiltrate was achieved using ultrasonic nebulisation combined with ICP-MS. This technique allows detection of platinum at the 0.001 microg Pt/ml level in only 100 microl of matrix. Assays in blood and plasma utilised a standard Meinhardt nebuliser and spray chamber, achieving detection limits of 0.1 microg Pt/ml in 100 and 200 microl of matrix, respectively. The assays were validated (accuracy and precision within +/- 15%) over the concentration ranges: 0.001-0.250 microg Pt/ml in plasma ultrafiltrate and 0.1-10 microg Pt/ml for plasma and whole blood. The effect of sample digestion. dilution, long term frozen storage and quantitation in the presence of 5-FU were also investigated and validated. The method was used to monitor platinum exposure following oxaliplatin administration (130 mg/m2) to cancer patients. Following a 2 h i.v. infusion, peak platinum levels declined in a triphasic manner in all blood compartments. Free platinum was detected in plasma ultrafiltrate at low levels (0.001 0.010 microg Pt/ml) for up to 3 weeks. In conclusion, a highly sensitive and specific assay has been developed for the determination of platinum in biofluids. This method enabled characterisation of the long term exposure to platinum in patients following oxaliplatin treatment.

Dose regimen adjustment for milrinone in congestive heart failure patients with moderate and severe renal failure.

This study was designed to test a proposed dose modification for intravenous milrinone in congestive heart failure patients (CHF, NYHA I-II) with either moderate or severe renal impairment. All the patients were administered an intravenous loading dose of drug at 50 micrograms kg-1 over 10 min. This was followed by an 18 h maintenance infusion of milrinone at 0.45 or 0.35 micrograms kg-1 min-1 for the moderate (chromium-EDTA clearance of 31-75 mL min-1, n = 10) and severe renally impaired subjects (chromium-EDTA of clearance 10-30 mL min-1, n = 11), respectively. Plasma and urine samples were collected for up to 34 h and analysed for parent drug by validated HPLC methods. The mean (+/- s.d.) steady-state plasma concentrations of milrinone were within the therapeutic range (100-300 ng mL-1) for both groups, with values of 239 +/- 71 ng mL-1 and 269 +/- 32 ng mL-1 for the moderate and severe patients, respectively. No statistical differences were observed between the steady-state values for the two groups. With the exception of two patients per group, individual steady-state levels were also within the therapeutic range. Those outside the nominal range showed steady-state levels, ranging between 308 and 353 ng mL-1, that were not associated with any serious adverse events.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition of milrinone in patients after cardiac surgery.

We have evaluated the disposition of milrinone in seven patients with low cardiac output after elective cardiac surgery involving cardiopulmonary bypass. Patients received a loading dose of milrinone 50 micrograms kg-1 given over 10 min followed immediately by an infusion of 0.5 microgram kg-1 min-1, continued for a minimum of 5 h. Plasma concentrations of milrinone were measured at designated intervals during the infusion and for 6 h after its termination, by high pressure liquid chromatography. Concentrations greater than 100 ng ml-1 were produced in all patients within 2 min of starting the loading dose and were maintained for the duration of the infusion. Volume of distribution, clearance and terminal half-life were similar to those found in patients with chronic cardiac failure.

The effect of Miglycol 812 oil on the oral absorption of propranolol in the rat.

This work has examined the effect of Miglyol 812 oil and its composite fatty acids on the oral absorption of propranolol with reference to its intravenous (i.v.) pharmacokinetics. Propranolol hydrochloride, spiked with 4-(3) H labelled compound, was administered i.v. or orally to male Wistar rats and blood concentrations of parent material determined by liquid scintillation counting after extraction into toluene. An i.v. dose-linearity study indicated dose-independent pharmacokinetics for propranolol at 1-2 mg kg-1, with a mean Cls, Vss, MRTi.v. and t0.5 beta of 0.076 L min-1 kg-1, 4.74 L kg-1, 57.81 min and 47.10 min, respectively. At 5 mg kg-1, there was evidence of non-linearity with MRTi.v. increased by about 250%, Vss by 170% and t0.5 beta by 230% compared with the lower doses. After oral administration of propranolol (10 mg kg-1) in aqueous solution, with or without Tween 80 (6%), the mean absorption time (MAT) and terminal half-life were approximately 55 min and 86 min, respectively. The MAT for propranolol administered in a 50% octanoic and lauric acid (1:1 by weight) oil-in-water emulsion, stabilized with 6% Tween 80 (129-90 min), was significantly longer compared with that for a 50% Miglyol 812 oil-in-water emulsion containing the same surfactant (16.55 min). The terminal half-life of propranolol administered in the fatty acid formulation (128.96 min), unlike that for the Miglyol emulsion (54-37 min), was significantly longer compared with that observed after i.v. administration (t0.5 beta = 47 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary absorption of carboxyfluorescein in the rat.

The pulmonary absorption of the fluorescent marker 6-carboxyfluorescein (CF) has been characterized. CF was administered intratracheally (i.t.) as a fluid instillate to pentobarbitone-anaesthetized rats at doses of 0.5 and 2 mg kg-1. The absorption was characterized by both model-independent and model-dependent pharmacokinetic analyses of blood concentration data with reference to previous intravenous (i.v.) studies. The mean fraction available (F) of CF was 90 and 112% with a mean absorption time of 107 and 109 min for the lower and higher doses, respectively. The terminal half-life for the i.t. administered CF (73 and 83 min for the 0.5 and 2 mg kg-1 doses, respectively) was significantly longer (P less than 0.001) than after i.v. dosing (18 min). This indicates a slow pulmonary absorption of CF. Blood concentration-time profiles could not be adequately described by models involving a simple first-order absorption process; a model incorporating two simultaneous first-order inputs gave a much better description, its absorption rate constants differing by almost two orders of magnitude.