Michael S. Schwartz

Comparative Pharmacokinetics of Lovastatin, Simvastatin and Pravastatin in Humans

Twelve healthy male volunteers received single market‐image 40‐mg oral doses of lovastatin and simvastatin (both lactone prodrugs), or pravastatin (α β‐hydroxyacid) at 1 week intervals in a three‐way crossover study to quantify HMG‐CoA reductase inhibitors in plasma. Multiple plasma samples were collected up to 24 hours after the dose and assayed for active and total HMG‐CoA reductase inhibitors. After equal oral doses, higher plasma concentrations of HMG‐CoA reductase inhibitory activity after pravastatin than after either lovastatin of simvastatin (2–3 fold greater area under the concentration‐time curve) suggest a greater potential availability of pravastatin‐related inhibitory activity to peripheral tissues.

Determination of a cyclic hexapeptide, a novel antifungal agent, in human plasma by high-performance liquid chromatography with ion spray and turbo ion spray tandem mass spectrometric detection.

Methods for the determination of a semi-synthetic cyclic hexapeptide (I, MK-0991) in human plasma based on high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS-MS) detection using pneumatically assisted electrospray (ion spray, ISP) and turbo ion spray (TISP) interfaces were developed. Drug and internal standard (II, an isostere of I) were isolated from plasma by solid-phase extraction (SPE). The eluent from SPE was evaporated to dryness, the residue was reconstituted in mobile phase and injected into the HPLC system. The use of ISP, TISP and heated nebulizer (HN) interfaces as sample introduction systems were evaluated and showed that the heated nebulizer was not adequate for analysis due to thermal instability and/or adsorption of I and II to glass surfaces of the interface. Compounds I and II were chromatographed on a wide pore (300 A), 150x4.6 mm C8 analytical column, and the HPLC flow-rate of 1.2 ml/min was split 1:20 prior to introduction to the ISP or TISP interface of the mass spectrometric system. The MS-MS detection was performed on a PE Sciex API III Plus tandem mass spectrometer operated in selected reaction monitoring mode (SRM). The precursor-->product ion combinations of m/z 1093.7-->1033.6 and 1094.7-->1033.6 were used to quantify I and II, respectively, after chromatographic separation of the analytes. The assay was validated in the concentration range of 10-1000 ng/ml using ISP, and 2.5-500 ng/ml of plasma using TISP with good precision and adequate accuracy. The effects of HPLC mobile-phase components on the ionization efficiency and sensitivity of detection in the positive ionization mode, the evaluation of the matrix effect, and limitations in sensitivity of detection of I due to the formation of multiply charged species are presented.

Comparison of Plasma Profiles of Lovastatin (Mevinolin), Simvastatin (Epistatin) and Pravastatin (Eptastatin) in the Dog

SummaryLovastatin (mevinolin) [LV], simvastatin (epistatin) [SV] and pravastatin (eptastatin) [PVA] are indicated in the treatment of hypercholesterolaemia and are potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Beagle dogs were dosed orally with LV and SV (both lactones), PVA (a hydroxy acid), LVA (the β-hydroxy acid of LV) and SVA (the β-hydroxy acid of SV), in separate experiments. Measurement of enzyme inhibitory activities showed that the plasma concentrations were considerably higher after dosing with the hydroxy acids LVA, SVA and PVA than after the lactones LV and SV, for equivalent doses. Plasma samples were also assayed for active metabolites by a specific high performance liquid chromatography (HPLC) method; these were LVA and SVA, together with their 6′-β-hydroxy, 6′-β-hydroxymethyl, and 6′-exomethylene analogues. These metabolites were present in roughly equal concentrations after dosing with the lactones LV and SV. The unchanged drug was the major component after dosing with the hydroxy acids LVA, SVA and PVA. The major metabolite present after dosing with LVA and SVA was the 6′-exomethylene analogue. This work demonstrates a basic difference in plasma concentrations and metabolic profiles between the lactones LV and SV and the hydroxy acids LVA, SVA and PVA after oral administration to the dog.

Pharmacokinetics of laropiprant and glucuronide metabolite in patients with severe renal insufficiency.

Flushing symptoms limit the use of niacin as an effective treatment for dyslipidemia; laropiprant, a prostaglandin D2 receptor subtype 1 antagonist, reduces niacin-induced flushing and is being developed in combination with niacin. The aims of this study were to both determine the effect of renal insufficiency on plasma pharmacokinetics of laropiprant and to assess safety and tolerability in patients with severe renal insufficiency. This open-label study compared the pharmacokinetics of a single laropiprant 40-mg dose in 8 nondialyzed, severe renal insufficiency patients (RIs) with healthy matched subjects (HSs) (24-hour creatinine clearance <30 mL/min/1.73 m2 and >80 mL/min/1.73 m2 for RIs and HSs, respectively). In RIs, laropiprant was well tolerated and the area under the concentration time curve (AUC0-∞) was modestly higher (ratio of geometric least-squares means [GMR] for RIs to HSs was 1.58; 90% confidence interval [CI], 1.06-2.35); neither the maximum laropiprant plasma concentration (Cmax) nor the time to Cmax (Tmax) was significantly affected. The apparent terminal half-life (t1/2) was 26.0 and 14.8 hours for RIs and HSs, respectively (P = 0.007). Similarly, for the inactive laropiprant glucuronide metabolite, the GMR for AUC0-∞ was 2.17 (90% CI, 1.44-3.27), and the apparent t1/2 values were 25.3 to 14.5 hours (P = 0.037) in RIs and HSs, respectively. Renal insufficiency had no clinically significant effect on laropiprant pharmacokinetics. Because niacin and its metabolites are excreted through the kidneys, the combination of niacin with laropiprant should be used with caution in patients with renal impairment.

Determination of a peptide–doxorubicin, prostate-specific antigen activated prodrug, and its active metabolites in human plasma using high-performance liquid chromatography with fluorescence detection: Stabilization of the peptide prodrug with EDTA

A method for the determination of I, a peptide-doxorubicin conjugate that was evaluated for the treatment of prostate cancer, and two of its active metabolites, doxorubicin and leucine-doxorubicin is described. Blood samples were chilled immediately after being drawn in order to prevent ex vivo entry of the metabolites into red blood cells. EDTA (10 mg/ml final concentration) was used to prevent plasma-mediated degradation of the peptide portion of the prodrug. After the addition of internal standard, plasma was prepared for analysis using a C-8 solid-phase extraction column. In order to overcome secondary ionic interactions with the silica-based extraction column, the analytes were eluted with ammonium hydroxide in methanol. The extracts were evaporated to dryness, reconstituted, and assayed by step change, gradient, reverse phase HPLC with fluorescence detection. Two interfering metabolites found in post dose plasma were chromatographically separated by an adjustment of the mobile phase pH. The within-day reproducibility of the doxorubicin and leucine-doxorubicin chromatographic retention times was improved by a brief washing of the analytical column with 90% acetonitrile after each injection. The range of the standard curve was 12.5-1250 ng/ml for doxorubicin and 25-2500 ng/ml for I and leucine-doxorubicin.

Caspofungin exposure-response relationships in adult patients with mucosal or invasive candidiasis.

Caspofungin is an echinocandin antifungal agent administered once daily as an intravenous infusion. Relationships between caspofungin exposure and clinical efficacy and safety were investigated. End‐of‐infusion (CEOI) and trough (C24 hours) concentrations were obtained in 218 patients with mucosal (i.e., esophageal and/or oropharyngeal) candidiasis (MC) receiving caspofungin 35, 50, or 70 mg/day and 278 patients with invasive candidiasis (IC) receiving 50, 100, or 150 mg/day. Area under the plasma concentration–time curve (AUC0–24 hours) was obtained in a subset of MC patients (n = 99). Odds ratios were estimated for the association between log‐transformed PK and efficacy response and the occurrence of common adverse events. No pharmacokinetic or hybrid parameter (ratio of AUC:MIC, CEOI:MIC, C24 hours:MIC) was significantly correlated with overall treatment outcome in either MC or IC, although this patient population may exhibit confounding factors which masked a potential pharmacokinetic/pharmacodynamic relationship. An exploratory evaluation of MC identified significant pharmacokinetic correlations with endoscopic response, but not symptom response. Statistically significant associations were identified for IC patients with C. parapsilosis infections. Occurrence of clinical adverse events and/or laboratory abnormalities did not appear to be increased by higher caspofungin plasma concentrations. Caspofungin concentrations achieved with 50 mg/day are generally within the therapeutic window for the treatment of candidiasis.