Myrna Y. Munar

A Phase I trial of pulse calcitriol in patients with refractory malignancies: pulse dosing permits substantial dose escalation.

Calcitriol is the principal biologically active metabolite of vitamin D. Calcitriols activity against many neoplasms is well documented, but calcitriols therapeutic application has been hampered by predictable hypercalcemia when it is given daily. Because laboratory data has suggested that intermittent exposure to high levels of calcitriol may be sufficient to produce antiproliferative effects, the authors developed a Phase I trial to determine the maximal tolerated dose, dose‐limiting toxicity, and the pharmacokinetic profile of calcitriol given weekly by mouth.

Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic-pituitary-ovarian activity

BACKGROUND This study was conducted to determine whether increased body mass index (BMI) affects oral contraceptive (OC) pharmacokinetics and suppression of hypothalamic-pituitary-ovarian (HPO) axis activity. STUDY DESIGN Ovulatory reproductive-age women with normal weight (BMI <25 kg/m(2); n=10) and with obesity (BMI >30 kg/m(2); n=10) received OCs for two cycles (prospective cohort). Subjects were admitted for two 48-h inpatient stays at the beginning and end of the hormone-free interval. Ethinyl estradiol and levonorgestrel (LNG) levels were evaluated during both inpatient stays. Gonadotropin pulsatility (follicle-stimulating hormone and luteinizing hormone) was measured during the second inpatient stay. Estradiol (E(2)) and progesterone (P) were measured daily during inpatient stays and twice per week in Cycle 2. RESULTS BMI was greater in the obese compared to the normal-BMI group [37.3 kg/m(2) (SD, 6.0) vs. 21.9 kg/m(2) (SD, 1.6); p<.05]. The LNG half-life was significantly longer in the obese group (52.1+/-29.4 vs. 25.6+/-9.3 h, p<.05), which correlated with a lower maximum LNG concentration on Cycle 2, Day 1 [1.9 ng/mL (SD, 0.5) vs. 2.5 ng/mL (SD, 0.7)] and a longer time to reach steady state (10 vs. 5 days) in obese women. There were no significant differences in volume of distribution between groups. LH pulse parameters did not differ statistically between groups but trended toward greater HPO activity in the obese group. Additionally, more obese (6/10 vs. 3/10 normal BMI, p>.05) women exhibited E(2) levels consistent with development of a dominant follicle and P levels consistent with ovulation (2/10 vs. 1/10) during Cycle 2. CONCLUSIONS Compared to women with normal BMI, obese women exhibit differences in OC pharmacokinetics that are associated with greater HPO activity.

Daptomycin Pharmacokinetics in Adult Oncology Patients with Neutropenic Fever

ABSTRACT Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant Staphylococcus aureus. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means ± standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (Cmax) was 49.04 ± 12.42 μg/ml (range, 21.54 to 75.20 μg/ml), the 24-h plasma concentration was 6.48 ± 5.31 μg/ml (range, 1.48 to 29.26 μg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 ± 523.53 μg·h/ml (range, 164.64 to 3155.11 μg·h/ml), the volume of distribution at steady state was 0.18 ± 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 ± 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 ± 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 ± 20.66 h (range, 7.00 to 121.73 h), and the median time to Cmax was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 ± 0.02. All patients achieved Cmax/MIC and AUC from time zero to 24 h (AUC0-24)/MIC ratios for a bacteriostatic effect against Streptococcus pneumoniae. Twenty-seven patients (93%) achieved a Cmax/MIC ratio for a bacteriostatic effect against S. aureus, and 28 patients (97%) achieved an AUC0-24/MIC ratio for a bacteriostatic effect against S. aureus. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for S. pneumoniae and 90% of patients for S. aureus. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.

Analysis of tacrolimus and creatinine from a single dried blood spot using liquid chromatography tandem mass spectrometry.

Long term therapeutic drug monitoring and assessment of renal function are required in renal transplant recipients on immunosuppressant therapy such as tacrolimus. Dry blood spots (DBS) have been used successfully in the clinic for many years and offers a convenient, simple and non-invasive method for repeated blood tests. We developed and performed a preliminary validation of a method for the analysis of tacrolimus and creatinine from a single DBS using liquid chromatography-tandem mass spectrometric (LC-MS/MS). Tacrolimus and creatinine were extracted from a 6mm punch with a mixture of methanol/acetonitrile containing ascomycin and deuterated creatinine as internal standards. A 10 μl aliquot of the extract was analyzed directly after dilution for creatinine with normal phase high performance liquid chromatography and multiple reaction monitoring. The remainder of the extract was processed and analyzed for tacrolimus. The lower limit of quantification for tacrolimus was 1 ng/ml with accuracy of 0.34% bias and precision (CV) of 11.1%. The precision ranged from 1.33% to 7.68% and accuracy from -4.44% to 11.6% bias for the intra- and inter-day analysis. The lower limit of quantification of creatinine was 0.01 mg/dL with precision of 7.94%. Accuracy was based on recovery of additional creatinine spiked into whole blood samples and ranged from -2.45% bias at 5 mg/dL to 3.75% bias at 0.5 mg/dL. Intra- and inter-day precision was from 3.48 to 4.11%. The assay was further validated with DBS prepared from pediatric renal transplant recipients. There was excellent correlation between the levels of tacrolimus and creatinine obtained from the clinical laboratory and the DBS method developed. After additional validation, this assay may have a significant impact on compliance with medication intake as well as potentially lowering the cost associated with intravenous blood draws in clinical laboratories.

Interaction Between Cyclosporine and Grapefruit Juice Requires Long‐Term Ingestion in Stable Renal Transplant Recipients

Study Objective. To examine the effect of the concurrent administration of increasing amounts of grapefruit juice, an inhibitor of drug metabolism, on the steady‐state pharmacokinetics of cyclosporine.

Pharmacokinetics of Ganciclovir in a Patient Undergoing Hemodialysis

The pharmacokinetics and effect of hemodialysis on the clearance of ganciclovir were evaluated in a patient with cytomegalovirus (CMV) retinitis and pneumonitis requiring dialytic support. A dose of 300 mg ganciclovir (5 mg/kg) was administered by intravenous infusion over a 60-minute period. Blood samples were obtained over the next 10 hours and used to assess plasma ganciclovir concentrations. The patient underwent hemodialysis the following day during which paired arterial and venous blood samples were obtained to determine dialyzer clearance of this antiviral agent. High-performance liquid chromatography was used to quantify ganciclovir plasma concentrations. Ganciclovir levels declined in a monoexponential manner following infusion and prior to dialysis. The patients peak ganciclovir concentration was markedly elevated (20 micrograms/mL) compared with previously reported peak concentrations in patients with normal renal function. Similarly, the elimination half-life (t1/2) was increased (6.3 hours) in this patient compared with values reported in patients with normal renal function. The volume of distribution (0.21 L/kg) and total body clearance prior to hemodialysis (35.5 mL/min) were diminished in this patient. Hemodialysis reduced ganciclovir levels by approximately 62% with an extraction coefficient of 0.29 resulting in a dialyzer clearance of 48.3 mL/min. This supports supplementation of ganciclovir in patients receiving this antiviral agent when they are undergoing hemodialysis. Additionally, close monitoring of ganciclovir concentrations in patients with abnormal renal function is necessary in order to make appropriate dosage adjustments.

Aprepitant Pharmacokinetics and Assessing the Impact of Aprepitant on Cyclophosphamide Metabolism in Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation

Aprepitant, a neurokinin antagonist, is an effective antiemetic agent in chemotherapy for delayed nausea and vomiting. The study objective was to evaluate the pharmacokinetics of aprepitant and concurrent cyclophosphamide (CY), often a component of hematopoietic stem cell transplant (HSCT) conditioning regimen, in cancer patients undergoing HSCT. Forty subjects were randomized to either aprepitant or placebo in addition to standard antiemetics. Aprepitant or placebo was started 1 hour before the first chemotherapy or radiation dose for HSCT conditioning and administered daily until 4 days after infusion of the hematopoietic cell graft (for a total of 10–12 days). Serial blood samples were collected for aprepitant and CY plus 2 important CY metabolites. The results indicate that aprepitant is well absorbed and does not auto‐induce its metabolism. No significant drug interaction was observed with CY or its metabolites. A significant portion of the patients had subtherapeutic aprepitant concentrations; however, chemotherapy‐induced nausea and vomiting were effectively managed. No dosage adjustment was necessary, and administration of aprepitant in HSCT at the prescribed dosage of 125 mg orally on day 1 and 80 mg orally on each consecutive day through day +4 after HSCT was well tolerated with no significant changes in CY pharmacokinetic parameters.

Pharmacokinetic study of lipoic acid in multiple sclerosis: Comparing mice and human pharmacokinetic parameters

Lipoic acid is a natural anti-oxidant available as an oral supplement from a number of different manufacturers. Lipoic acid administered subcutaneously is an effective therapy for murine experimental autoimmune encephalomyelitis, a model of multiple sclerosis. The aim of this study was to compare serum lipoic acid levels with oral dosing in patients with multiple sclerosis with serum levels in mice receiving subcutaneous doses of lipoic acid. We performed serum pharmacokinetic studies in patients with multiple sclerosis after a single oral dose of 1200 mg lipoic acid. Patients received one of the three different racemic formulations randomly: tablet (Formulation A) and capsules (Formulations B and C). Mice pharmacokinetic studies were performed with three different subcutaneous doses (20, 50 and 100 mg/kg racemic lipoic acid). The pharmacokinetic parameters included Maximum Serum Concentrations (Cmax in μg/ml) and area under the curve 0—infinity (AUC 0—infinity in μg*min/ml). We found mean Cmax and AUC 0—infinity in patients with multiple sclerosis as follows: group A (N = 7) 3.8 ± 2.6 and 443.1 ± 283.9; group B (N = 8) 9.9 ± 4.5 and 745.2 ± 308.7 and group C (N = 8) 10.3 ± 3.8 and 848.8 ± 360.5, respectively. Mean Cmax and AUC 0—infinity in the mice were: 100 mg/kg lipoic acid: 30.9 ± 2.9 and 998 ± 245; 50 mg/kg lipoic acid: 7.6 ± 1.4 and 223 ± 20; 20 mg/kg lipoic acid: 2.7 ± 0.7 and 119 ± 33. We conclude that patients taking 1200 mg of lipoic acid from two of the three oral formulations achieved serum Cmax and AUC levels comparable to that observed in mice receiving 50 mg/kg subcutaneous dose of lipoic acid, which is a highly therapeutic dose in experimental autoimmune encephalomyelitis. A dose of 1200 mg oral lipoic acid can achieve therapeutic serum levels in patients with multiple sclerosis.

Effect of grapefruit juice on cyclosporin A pharmacokinetics in pediatric renal transplant patients

Abstract: Cyclosporin A (CsA) is an important immunosuppressant that is prone to numerous drug interactions. Grapefruit juice has been investigated, as a possible adjunct to CsA dosing in adult renal transplant recipients, to decrease CsA metabolism and reduce dosages. This study investigated this combination in pediatric renal transplant patients. Six stable pediatric renal transplant patients were entered into an open‐label, four‐period cross‐over study in which patients were given their current CsA dose as either an oral solution (CsA‐Sol) or a microemulsion (CsA‐ME). In addition, drugs were administered concurrently with water or grapefruit juice. Steady‐state pharmacokinetic profiles were taken during each of the four periods. Following the concurrent administration of grapefruit juice, CsA whole‐blood 12‐h trough levels were significantly increased during CsA‐Sol dosing. Furthermore, the CsA elimination rate constant was significantly reduced during the same period. After CsA‐ME dosing, no differences in CsA pharmacokinetics were found between concurrent water or grapefruit ingestion. Grapefruit juice co‐administration reduced the production of CsA metabolites, AM1 and AM9, during CsA‐Sol dosing. No changes in CsA metabolite production were found when patients were given CsA‐ME with grapefruit juice as compared with water. Hence, alterations in CsA absorption and elimination occur with concurrent grapefruit juice ingestion when stable pediatric renal transplant patients are taking the oral CsA solution, but not the microemulsion formulation. These changes may be mediated by alterations in intestinal or hepatic metabolism, or drug absorption. The effect of grapefruit juice on CsA absorption is not readily predictable in these patients.

Meropenem pharmacokinetics in a patient with multiorgan failure from meningococcemia undergoing continuous venovenous hemodiafiltration

Meropenem is a carbapenem antibiotic with a broad antibacterial spectrum of activity. Its main route of elimination is through the kidneys, with 63% of the drug excreted unchanged in the urine. Meropenem clearance is diminished in renal impairment; therefore, doses need to be adjusted in patients with varying degrees of renal function. An appropriate dose of meropenem for patients undergoing continuous venovenous hemodiafiltration (CVVHDF) is unknown. We evaluated the pharmacokinetics of meropenem in a patient with fulminant meningococcemia undergoing CVVHDF. Meropenem concentrations in serial venous, arterial, and ultrafiltrate samples after a 1 g intravenous dose were measured using high-performance liquid chromatography (HPLC). Meropenem clearance was found to be 129.36 mL/min and 141.29 mL/min for every 8- and 12-hour dosing, respectively. Trough levels were above the MIC90 for Neisseria meningitidis and most anaerobic pathogens. We recommend that meropenem 1 g intravenously every 12 hours be used as the initial dose in patients undergoing CVVHDF. Differences between meropenem clearance during CVVHDF and other forms of renal replacement therapy are discussed.