R. S. Addison

A Phase I Biological and Pharmacologic Study of the Heparanase Inhibitor PI-88 in Patients with Advanced Solid Tumors

Purpose: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study. Experimental Design: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2). Results: Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and Cmax correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for ≥6 months. Conclusion: The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.

Influence of grapefruit juice on cisapride pharmacokinetics

Grapefruit juice increases the oral bioavailability of several drugs metabolized by cytochrome P450 3A4. This study investigated the influence of grapefruit juice on the pharmacokinetics of oral cisapride, a substrate of CYP3A4.

Pharmacokinetics and bioequivalence evaluation of two fixed-dose tablet formulations of dihydroartemisinin and piperaquine in Vietnamese subjects

ABSTRACT The two fixed-dose combinations of dihydroartemisinin and piperaquine (Artekin and Arterakine) were found to be bioinequivalent in healthy Vietnamese subjects. However, because the peak plasma concentrations and areas under the concentration-time curves of dihydroartemisinin and piperaquine were only marginally different between the two formulations, similar therapeutic efficacies are expected in the treatment of malaria infections.

Monitoring salivary lamotrigine concentrations

Lamotrigine concentrations were measured simultaneously (as far as was feasible) in stimulated and unstimulated saliva samples, and in plasma, from seven adult volunteers over a 32 h period following a single 50 mg dose of the drug, and in 20 children and adolescents during the course of routine antiepileptic therapy. In individuals there was a close correlation between the measurements at least 2 h after ingestion of the drug. Concentrations in stimulated and unstimulated saliva were similar; the stimulation produced little change in the saliva secretion rate. The saliva-to-plasma concentration ratio increased linearly by 0.78% for each 1 mg/L plasma lamotrigine concentration, with a mean value of 48.8% at a plasma lamotrigine concentration of 10 mg/L. With appropriate precautions as to the timing of saliva collections, and a single plasma lamotrigine concentration measurement to calibrate the salivary values in the individual, salivary lamotrigine concentration measurement appears to be a practicable approach to therapeutic drug monitoring. This has significant implications for the elucidation of the pharmacokinetics of lamotrigine in the paediatric population.

Valproate metabolism during valproate-associated hepatotoxicity in a surviving adult patient

The plasma profiles of valproate (VPA), its beta-oxidation metabolites E-2-en-VPA and 3-oxo-VPA and its terminal desaturation metabolite 4-en-VPA, have been measured in a patient receiving NaVPA 1000 mg twice per day from early in the course of serious hepatotoxicity and for 2 weeks after the drug was stopped. Concurrent profiles of liver, renal and haematological function parameters were available. Relative to concurrent plasma VPA concentrations, E-2-en-VPA concentrations were not different to those of the VPA-treated epileptic population at any stage of the illness, whereas 3-oxo-VPA concentrations relative to concurrent VPA concentrations were abnormally high early in the toxicity, abnormally low at its peak (3-5 days later), and comfortably within normal limits for the treated epileptic population late in the recovery phase (9-13 days from the onset). When measurable, plasma 4-en-VPA concentrations were not elevated. The elimination half-life of VPA during the recovery phase was 100 h, which is some 6-12 times greater than values reported for this parameter in normal patients. These data clearly define, in this patient, a link between idiosyncratic VPA-associated hepatotoxicity at its onset and peak and the later stages of VPA beta-oxidation. Whether the beta-oxidation abnormalities are causative or a consequence of an as yet undefined defect is unknown. In this patient, 4-en-VPA was unlikely to have been involved in the pathogenesis of the toxicity.

Validated LC-MS/MS assay for the quantitative determination of vardenafil in human plasma and its application to a pharmacokinetic study.

A sensitive high-performance liquid chromatography-tandem mass spectrometric (HPLC-MS/MS) assay has been developed for the quantitative analysis of vardenafil in human plasma. Vardenafil and the internal standard, alprazolam, were extracted from 0.2 mL aliquots of alkalinized plasma by a single solvent extraction into hexane : dichloromethane. Reversed-phase chromatographic separation was affected by gradient elution with mobile phases consisting of 10 mM ammonium formate pH 7.0 (solvent A) and methanol (100%, solvent B), delivered at a flow rate of 0.4 mL/min. The analytes were detected by using an electrospray ion source on a 4000 QTrap triple quadrupole mass spectrometer operating in positive ionization mode. The mass transitions were m/z 489.3 --> 312.2 for vardenafil and m/z 309.2 --> 281.0 for alprazolam. The assay was linear over the concentration range of 0.2-100 ng/mL, with correlation coefficients > or = 0.995. The intra- and inter-day precision was less than 5.4% in terms of relative standard deviation and the accuracy was within 12.7% in terms of relative error. The lower limit of quantitation was set at 0.2 ng/mL. The high sensitivity and acceptable performance of the assay allowed its application to the analysis of plasma samples obtained following the oral administration of vardenafil to healthy male volunteers in a pharmacokinetic study.

Disposition of naproxen, naproxen acyl glucuronide and its rearrangement isomers in the isolated perfused rat liver

1. An isolated perfused rat liver (IPRL) preparation was used to investigate separately the disposition of the non-steroidal anti-inflammatory drug (NSAID) naproxen (NAP), its reactive acyl glucuronide metabolite (NAG) and a mixture of NAG rearrangement isomers (isoNAG), each at 30 μg NAP equivalents ml−1 perfusate (n = 4 each group). 2. Following administration to the IPRL, NAP was eliminated slowly in a log-linear manner with an apparent elimination half-life (t1/2) of 13.4±4.4 h. No metabolites were detected in perfusate, while NAG was the only metabolite present in bile in measurable amounts (3.9 ± 0.8% of the dose). Following their administration to the IPRL, both NAG and isoNAG were rapidly hydrolysed (t1/2 in erfusate = 57 ± 3 and 75 ± 14 min respectively). NAG also rearranged to isoNAG in the perfusate. Both NAG and isoNAG were excreted intact in bile (24.6 and 14.8% of the NAG and isoNAG doses, respectively). 3. Covalent NAP-protein adducts in the liver increased as the dose changed from NAP to NAG to isoNAG (0.20 to 0.34 to 0.48% of the doses, respectively). Similarly, formation of covalent NAP-protein adducts in perfusate were greater in isoNAG-dosed perfusions. The comparative results suggest that isoNAG is a better substrate for adduct formation with liver proteins than NAG.

Midazolam metabolism: Implications for individualised dosing?

To compare the clearance of midazolam and its metabolites in critically ill paediatric and adult patients.

In Vitro Placental Perfusion

The placenta is a relatively short-lived tissue that is of absolute importance to the generation of future humans and indeed to the survival of all species of mammals. During its existence, it is responsible for a number of complex functions, which are normal features of separate organs and tissues within the body. Such functions include gas exchange, solute exchange, detoxification, primary endocrine functions, secondary endocrine functions and hormone degradation. In order to study the detailed biochemistry and physiology of full term placentae, in-vitro perfusion systems for this tissue were reported as long ago as 1922 (Schmitt), although the simplification of the procedure to incorporate the use of single placental lobules was not reported until much later (Panigel, 1962). The technique has been further refined since those early reports and has since been used to answer a wide range questions about normal and abnormal placental metabolism. In addition the technique has been applied to fields as diverse as toxicology, endocrinology and pharmacology, in order to determine the transfer kinetics of a range of xenobiotics. In-vitro placental perfusion using full-term human placentae has now been performed by our group in a number of locations for a period of years. As a result of a number of enquiries from other groups interested in establishing the procedure, it seemed timely to report our recent “success rate” with the procedure and to review the major factors which require attention to ensure reasonable performance of this demanding procedure. We report here an analysis of the outcomes of ninety such perfusions attempted over the last two-year period (mid 1996-mid 1998). We also proffer a technique, which may be found valuable in attempts to normalise results for such parameters as oxygen consumption between perfusions as well as affording the prospect of earlier prediction of perfusion instability.