Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients: Twice Daily Versus Once Daily Dosing

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72008/1/j.1600-6143.2004.00383.x.pd

In vitro in vivo relations for the parenteral liposomal formulation of Amphotericin B: A biorelevant and clinically relevant approach

There is limited information on how to perform in vitro release tests for intravenously administered parenteral formulations and how to relate the in vitro release with an in vivo pharmacokinetic parameter after the administration of the formulation. In this study, the effect of hydrodynamics (using sample and separate and continuous flow conditions) and medium components (synthetic surfactants, albumin and buffers) on the release of Amphotericin B from the liposomal Ambisome® formulation were investigated. Pharmacokinetic modeling of plasma concentration profiles from healthy subjects administered Ambisome® was used to estimate the in vivo release rate constant of drug from the formulation in order to compare it with the in vitro release profiles. With the estimated in vivo and in vitro release rate constants, release profiles were generated. Two approaches were followed: comparison of in vivo and in vitro release rate constants and comparison of the area under the percent release-time curve from observed in vitro release data and simulated in vivo release data. Albumin was found to be most critical factor for the release of the drug by having a negative effect on the amount of Amphotericin B released. The release profiles obtained with the sample and separate method in both Krebs Ringer buffer- and Phosphate Saline buffer - albumin 4.0% w/v were predictive of the in vivo release profiles in healthy subjects. Determining the factors affecting drug release from parenteral formulations and relating the release profiles to a pharmacokinetic parameter in vivo supports the development of in vitro in vivo relations for parenteral products

Safety, Tolerability, and Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Pediatric Patients

The safety, tolerability, and pharmacokinetics of the liposomal formulation of amphotericin B (L-AMB) were evaluated in 40 immunocompromised children and adolescents. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study with 10 to 13 patients in each of the four dosage cohorts. Each cohort received daily dosages of 2.5, 5.0, 7.5, or 10 mg of amphotericin B in the form of L-AMB per kg of body weight. Neutropenic patients between the ages of 1 and 17 years were enrolled to receive empirical antifungal therapy or treatment of documented invasive fungal infections. The pharmacokinetic parameters of L-AMB were measured as those of amphotericin B by high-performance liquid chromatography and calculated by noncompartmental methods. There were nine adverse-event-related discontinuations, four of which were related to infusions. Infusion-related side effects occurred for 63 (11%) of 565 infusions, with 5 patients experiencing acute infusion-related reactions (7.5- and 10-mg/kg dosage levels). Serum creatinine levels increased from 0.45 ± 0.04 mg/dl to 0.63 ± 0.06 mg/dl in the overall population (P = 0.003), with significant increases in dosage cohorts receiving 5.0 and 10 mg/kg/day. At the higher dosage level of 10 mg/kg, there was a trend toward greater hypokalemia and vomiting. The area under the concentration-time curve from 0 to 24 h (AUC(0–24)) values for L-AMB on day 1 increased from 54.7 ± 32.9 to 430 ± 566 μg · h/ml in patients receiving 2.5 and 10.0 mg/kg/day, respectively. These findings demonstrate that L-AMB can be administered to pediatric patients at dosages similar to those for adults and that azotemia may develop, especially in those receiving ≥5.0 mg/kg/day

Disposition of quinapril and quinaprilat in the isolated perfused rat kidney

An isolated perfused rat kidney model was used to probe the renal disposition of quinapril and quinaprilat after separate administration of each drug species. Control studies were performed with drug-free perfusate ( n=8 ) and perfusate containing quinapril ( n=9 ) quinaprilat ( n=7 ) at initial drug concentrations of 1000 ng/ml (including corresponding tracer levels of tritiated drug). Physiologic parameters were within the normal range of values for this technique and were stable for the duration of each experiment. Quinapril and quinaprilat concentrations were determined in perfusate, urine, and perfusate ultrafiltrate using a specific and sensitive reversed-phase HPLC procedure with radiochemical detection, coupled to liquid scintillation spectrometry. Perfusate protein binding was determined using an ultrafiltration method at 37°C. The total renal learance of quinapril ( CLr ) was calculated as Dose/AUC (0-∞), and is represented by the sum of its urinary and metabolic clearances. The urinary clearances ( CLe ) of quinapril and quinaprilat were calculated as urinary excretion rate divided by midpoint perfusate concentration for each respective species. Of the total renal clearance for quinapril ( CLr =4.49 ml/min), less than 0.1% was cleared as unchanged drug ( CLe =0.004 ml/min); over 99% of the drug was cleared as quinaprilat formed in the kidney. The clearance ratio of quinapril [ CR=CLr/(fu·GFR )] was 41.0, a value representing extensive tubular secretion into the renal cells. Following quinaprilat administration, the clearance ratio of metabolite [ CR=CLe/(fu β GFR) ] was 3.85, indicating a net secretion process for renal elimination.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45050/1/10928_2006_Article_BF02354286.pd

Tubular transport mechanisms of quinapril and quinaprilat in the isolated perfused rat kidney: Effect of organic anions and cations

The clearance mechanisms of quinapril and quinaprilat were probed using an isolated perfused rat kidney model. Sixty-four experiments were performed with drug in the absence and presence of classic inhibitors of the organic acid (i.e., probenecid and p-aminohippurate) and organic base (i.e., tetraethylammonium and quinine) transport systems of the proximal tubule. Initial perfusate concentrations of quinapril and quinaprilat were approximately 2.36 μM (or 1000 ng/ml), and transport inhibitors were coperfused at 100–10,000 times the drugs' initial μM concentrations. Quinapril and quinaprilat concentrations were determined in perfusate, urine, and perfusate ultrafiltrate using a reversed-phase HPLC procedure with radiochemical detection, coupled to liquid scintillation spectrometry. Perfusate protein binding was determined using an ultrafiltration method at 37°C. Overall, the clearance ratios of quinapril (total renal clearance divided by fu·GFR ) and quinaprilat (urinary clearance divided by fu·GFR ) were significantly reduced, and in a dose-dependent manner, by the coperfusion of organic acids but not organic bases. The data demonstrate that the organic anionic secretory system is the primary mechanism by which quinapril and quinaprilat are transported into and across renal proximal cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45053/1/10928_2006_Article_BF02353517.pd

Renal transport kinetics of furosemide in the isolated perfused rat kidney

Direct quantitative data and corresponding theory are provided for the effect of protein binding on the renal transport of furosemide. Drug studies were performed with various combinations of bovine serum albumin and dextran. This resulted in a percent unbound ( fu ) of furosemide ranging from 0.785 to 85.8%. The corrected renal ( CLr/GFR ) and secretion ( CLs/GFR ) clearances of furosemide were observed to increase with percent free, but in a nonproportional manner. Plots of CLr/GFR or CLs/GFR vs. fu appeared to have a prominent y intercept as well as a convex ascending curve. In addition, the excretion ratio [ ER=CLr/ (fu · GFR) ] was reduced from 60.8 to 8.72 as fu increased. Overall, the data were best fitted to a model in which two Michaelis-Menten terms wre used to describe renal tubular transport, and secretion was dependent upon free drug concentrations in the perfusate. The results demonstrate that the renal mechanisms of furosemide excretion are more complex than previously reported and that active secretion may involve two different transport systems over the concentration range studied.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45036/1/10928_2005_Article_BF01065259.pd

Tacrolimus pharmacology and nonclinical studies: from FK506 to protopic.

Tacrolimus (FK506) is a calcineurin inhibitor with potent immunomodulating properties. It has been marketed worldwide since 1993-1994 for the rejection of liver and kidney transplants (Prograf). The pharmacologic properties of tacrolimus resulted in its development as an ointment for the treatment of atopic dermatitis. An outline of nonclinical pharmacology studies that provided a rationale for this development is presented. The key nonclinical toxicology-safety studies that supported clinical efficacy/safety trials are also discussed. Taken collectively, these studies contributed to the marketing approval of 0.03% and 0.1% tacrolimus ointment (Protopic) as a first in class treatment for atopic dermatitis