Terminal Disposition Half-life Research Articles

Pharmacokinetics of single- and multiple-dose flumatinib in patients with chronic phase chronic myeloid leukemia.

Flumatinib is a novel, oral breakpoint cluster region-abelson (BCR-ABL) tyrosine kinase inhibitor that has demonstrated manageable safety and promising efficacy in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). This study evaluated the pharmacokinetic (PK) profiles of flumatinib mesylate tablets at a dose of 400 mg and 600 mg in patients with CML-CP. The study was registered at chictr.org Identifier (ChiCTR2100044700). In this open-label, pharmacokinetic study, eligible patients were administered a single-dose of flumatinib 400 mg or 600 mg on day 1, followed by 2-day washout and 8 consecutive days of once-daily administration. Serial plasma samples were assayed for flumatinib and its metabolites (N-demethylate metabolite M1 and amide-bond hydrolytic metabolite M3). Twenty-nine patients were assigned to flumatinib 400 mg (n=14) or 600 mg (n=15). Serum concentrations of flumatinib reached maximum measured plasma concentration (Cmax) at a median time of 2 hours after each single dose, and then eliminated slowly with a mean apparent terminal disposition half-life (t1/2) from 16.0 to 16.9 hours. Following single- and multiple-dose administration, flumatinib exposure (Cmax, area under the concentration-time curve from 0 to t hours (AUC0-t), area under the concentration-time curve from 0 hours to infinity (AUC0-∞)) increased in an approximately dose-proportional manner. There was approximately 4.1- and 3.4- fold drug accumulation at steady-state after multiple-dose administration at 400 mg and 600 mg, respectively. The drug-related AEs associated with both treatments were primarily low-grade and tolerable events. Analysis of PK parameters indicated that flumatinib exposure increased in an approximately dose-proportional manner. Further research needs to be conducted in a large sample-size study.

Sirolimus Pharmacokinetics in Early Postmyeloablative Pediatric Blood and Marrow Transplantation

This study examined the pharmacokinetics of sirolimus in pediatric allogeneic blood and marrow transplantation (BMT) recipients in the presence and absence of concomitant fluconazole. Forty pediatric BMT recipients received a daily oral dose of sirolimus and a continuous i.v. infusion of tacrolimus for graft-versus-host disease prophylaxis. Fluconazole was administered i.v. to 19 patients and orally to 6 patients. Full pharmacokinetic profiles of sirolimus within a single dosing interval were collected. Whole-blood sirolimus concentrations were measured by HPLC/mass spectrometry. Noncompartmental analysis was performed using WinNonlin. Nonlinear mixed-effects pharmacokinetic models were developed using NONMEM following standard procedures. The mean ± SD sirolimus trough level before the dose (C0) was 8.0 ± 4.6 ng/mL (range, 1.8-21.6 ng/mL). The peak concentration was 19.9 ± 11.8 ng/mL (range, 3.9-46.1 ng/mL), and the trough level 24 hours later (C24) was 9.1 ± 5.3 ng/mL (range, 1.0-19.1 ng/mL). The terminal disposition half-life (T1/2) was 24.5 ± 11.2 hours (range, 5.8-53.2 hours), and the area under the concentration-versus-time curve (AUC0-24) was 401.1 ± 316.3 ng·h/mL (range, 20.7-1332.3 ng·h/mL). In patients at steady state, C0 and C24 were closely correlated (R2 = 0.77) with a slope of 0.99, indicating the achievement of steady state. C24 was 1.7-fold greater (P = .036) and AUC0-24 was 2-fold greater (P = .012) in Caucasian patients (n = 22) compared with Hispanic patients (n = 9). The average apparent oral clearance was 3-fold greater (P = .001) and the apparent oral volume of distribution was 2-fold greater (P = .018) in patients age ≤12 years compared with those age >12 years. C24 was significantly lower in patients (n = 10) who developed grade III-IV aGVHD (n = 10) than in those with grade 0-II aGVHD (n = 22) (6.1 ± 2.9 ng/mL versus 9.4 ± 5.5 ng/mL; P = .044). Dose-normalized sirolimus trough concentrations were significantly higher in patients receiving concomitant fluconazole therapy compared with those not receiving fluconazole (C0: 3.9 ± 2.5 versus 2.4 ± 1.5 ng/mL/mg, P = .030; C24: 4.8 ± 3.3 versus 2.5 ± 1.7 ng/mL/mg, P = .018). This pharmacokinetic study of sirolimus in pediatric patients documents a large interindividual variability in the exposure of sirolimus. Steady-state trough blood concentrations were correlated with drug exposure. Trough concentrations were higher with a concomitant use of fluconazole and were higher in Caucasian patients than in Hispanic patients. Oral clearance was greater in children age ≤12 years than in older children and adolescents. With therapeutic drug monitoring, the majority (79%) of sirolimus trough levels could be maintained within the target range (3-12 ng/mL). This study provides a rationale and support for dose adjustments of sirolimus based on steady-state blood concentrations aimed at achieving a target concentration to minimize toxicity and maximize therapeutic benefits in pediatric BMT recipients.

449PD - Phase 1 Dose-Escalation Trial of the Investigational Hedgehog (HH) Pathway Inhibitor Tak-441 in Patients with Advanced Solid Tumors

ABSTRACT Background Dysregulation of the Hh pathway is a principal event in the carcinogenesis of multiple tumor types, including basal cell carcinoma. TAK-441 is an investigational, orally-available inhibitor of the G protein-coupled receptor Smoothened, a component of the Hh signalling cascade. Methods This study (NCT01204073) was designed to determine safety, maximum tolerated dose (MTD) and maximum feasible dose (MFD) in patients with advanced solid tumors. Cycles consisted of 3 weeks continuous dosing, with a single-dose cycle 1 lead-in, followed by 7 d pharmacokinetics (PK). Dose escalation (DE) proceeded in a modified 3 + 3 fashion. Radiographic tumor assessments were performed after cycles 2, 4, and every 4 cycles thereafter. Results Thirty-two patients were enrolled in the DE phase, median age 59 y (range 28–82), and treated with doses from 50–1600 mg daily. TAK-441 concentrations were quantifiable in plasma after the starting 50 mg dose, with total exposure increasing dose-proportionally to 800 mg. Maximum plasma concentration typically was reached 3 h post-dose. The median terminal disposition half-life was 15 h (range 6–35 h). DLTs of Gr 3 fatigue and muscle spasms were observed in 1 pt at the 1600 mg dose. Six subjects discontinued due to an adverse event (AE) including a patient who suffered a fatal cerebral hemorrhage in cycle 4 related to 50 mg TAK-441. Most common treatment-emergent AEs were muscle spasms (44%), dysguesia (41%), nausea (41%), fatigue (38%) and constipation (28%). The MFD is 1600 mg and the MTD has not been reached. Four patients remained on trial for >10 cycles, and 3 patients continue on treatment. Response and PK/PD data will be presented. Conclusions TAK-441 was well-tolerated up to an MFD of 1600 mg taken once daily. A dose expansion cohort has been initiated at 800 mg in patients with untreated basal cell carcinoma. Disclosure S.G. Eckhardt: Consultancy, Research funding and Speakers Bureau/Advisory Committee for Millennium/Takeda. S. Kuan: Employment with Millennium Pharmaceuticals, Inc. J. Yu: Employment and consultancy for Millennium. L.S. Rosen: Research support from Millennium. All other authors have declared no conflicts of interest.

Effects of Hepatic Dysfunction on the Single-Dose Pharmacokinetics of Fesoterodine

Fesoterodine, a new antimuscarinic for the treatment of overactive bladder, is rapidly and extensively hydrolyzed by nonspecific esterases to its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). The elimination of 5-HMT involves metabolism and renal excretion. The plasma and urinary pharmacokinetics of 5-HMT and its inactive carboxy (SPM 5509), N-desisopropyl (SPM 7789), and carboxy-N-desisopropyl (SPM 7790) metabolites were investigated after a single oral dose of 8 mg of fesoterodine in 8 male subjects with moderate hepatic cirrhosis (Child-Turcotte-Pugh class B) and 8 matched healthy controls. The estimated mean ratios (95% confidence interval) of the area under the curve extrapolated to infinity after dosing (AUC(0-∞)), cumulative urinary excretion up to 48 hours after dosing (Ae(0-48)), maximum observed concentration (C(max)), and apparent terminal disposition half-life (t(1/2)) of 5-HMT for cirrhotic and healthy subjects were 2.2 (1.5-3.1), 2.5 (1.7-3.8), 1.4 (1.0-1.9), and 1.1 (0.8-1.3), respectively. In subjects with hepatic cirrhosis, AUC(0-∞) and Ae(0-48) of 5-HMT increased approximately 2-fold; the increase in C(max) was smaller, and t(1/2) was unaffected. AUC and C(max) of the inactive carboxy metabolites, SPM 5509 and SPM 7790, were reduced reciprocally by about 50%, whereas exposure to the dealkylated metabolite, SPM 7789, increased about 2-fold. Fesoterodine 8 mg was equally well tolerated in both groups. The results indicate that moderate hepatic cirrhosis reduces 5-HMT clearance, with an apparent effect on the carboxylation pathway and not on dealkylation.

Dronedarone: An Alternative to Amiodarone?

To review the safety and efficacy of the newly approved, mixed-activity antiarrhythmic dronedarone (classes I-IV) versus its parent compound comparator, amiodarone (class III, with mixed activity). A MEDLINE/PUBMED (January 1966 to March 2010) and International Pharmaceutical Abstract (January 1975 to March 2010) search of English language papers in addition to a bibliographic search of retrieved papers. All human studies of dronedarone, alone or in combination with amiodarone, were reviewed. Approved in July 2009, dronedarone is a new antiarrhythmic agent indicated to reduce the risk of hospitalization for cardiac events in patients with paroxysmal or persistent atrial fibrillation or atrial flutter. Dronedarone has been viewed as a potential therapeutic alternative for amiodarone because of a lower risk for pulmonary, thyroid, and dermatologic adverse effects. Compared with amiodarone, dronedarone has poor bioavailability and a shorter terminal disposition half-life, which dictates a twice-daily dosing regimen. Furthermore, dronedarone failed to demonstrate superiority over amiodarone with respect to recurrence of atrial fibrillation in a comparative efficacy analysis. Dronedarone therapy is more costly and increases overall tablet burden. No dosage adjustments are required with dronedarone for renal impairment. Use of dronedarone is contraindicated in the presence of severe hepatic impairment. No serious organ-related toxicities (i.e., thyroid and pulmonary system) have been reported with use of dronedarone. Dronedarone as a niche drug may be a reasonable theoretical alternative for patients who cannot tolerate amiodarone or have underlying comorbidities that contraindicate amiodarone use (e.g., pulmonary, thyroid disease). However, dronedarone has not been studied in the vast majority of indications and patient populations in which amiodarone has been studied.

Single‐Dose Pharmacokinetics of Sustained‐Release Fampridine (Fampridine‐SR) in Healthy Volunteers and Adults With Renal Impairment

Fampridine-SR is a sustained-release formulation of fampridine (4-aminopyridine), a potassium channel blocker demonstrated to improve walking ability in patients with multiple sclerosis. This study evaluated the pharmacokinetics of fampridine and its metabolites after administration of fampridine-SR 10 mg in healthy volunteers and in subjects with mild, moderate, or severe renal impairment (5 per group). Analysis of variance was used to calculate 90% confidence intervals (CIs) for the ratios (impaired/healthy) of least squares mean in maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC). Clearance was primarily through urinary excretion. In renally impaired subjects, fampridine plasma concentrations were consistently higher than in healthy individuals: ratios for C(max) ranged from 166.5% to 199.9% for mild and severe renal impairment, respectively. AUC(0-infinity) ratios ranged from 175.3% to 398.7%, respectively, for mild and severe renal impairment. Mean terminal disposition half-life was 6.4 hours in healthy individuals, compared with 7.4, 8.1, and 14.3 hours in patients with mild, moderate, and severe renal impairment, respectively. Regression analysis confirmed the significant relationship between creatinine clearance and extent of exposure as quantified by AUC for fampridine and its metabolites, suggesting cautious use in patients with mild renal impairment and avoidance in cases of moderate or severe renal impairment.

Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of LXR‐623, a Novel Liver X‐Receptor Agonist, in Healthy Participants

Liver X-receptor (LXR) agonists have been postulated to enhance reverse cholesterol transport (RCT), a process believed to shuttle cholesterol from the periphery back to the liver. Enhancing RCT via the upregulation of cholesterol transporters such as the adenosine triphosphate-binding cassettes ABCA1 and ABCG1 could therefore inhibit the progression of atherosclerosis. LXR-623 is a synthetic ligand for LXRs alpha and beta that has shown promise in animal models of atherosclerosis. The authors present results from a single ascending-dose study of the safety, pharmacokinetics, and pharmacodynamics of LXR-623 in healthy participants. LXR-623 was absorbed rapidly with peak concentrations (C(max)) achieved at approximately 2 hours. The C(max) and area under the concentration-time curve increased in a dose-proportional manner. The mean terminal disposition half-life was between 41 and 43 hours independently of dose. LXR activation resulted in a dose-dependent increase in ABCA1 and ABCG1 expression. The effect of LXR-623 concentration on ABCA1 and ABCG1 expression was further characterized via a population pharmacokinetic-pharmacodynamic analysis, yielding EC(50) estimates of 526 ng/mL and 729 ng/mL, respectively. Central nervous system-related adverse events were observed at the 2 top doses tested. The pharmacodynamic effects described here are the first demonstration of "target engagement" by an LXR agonist in humans.

RGH-188, a d3/d2 dopamine receptor antagonist/partial agonist atypical antipsychotic candidate

Objectives:RGH-188 is an orally active, potent dopamine D3/D2 receptor antagonist/partial agonist atypical antipsychotic for the treatment of schizophrenia and bipolar mania.Results:RGH-188 displayed high affinity to human D3 receptors (Ki: 0.085 nM) and approximately six- and thirty-times less affinity to human D2, and 5-HT1A receptors. In various in vitro and in vivo assays RGH-188 behaved either as an antagonist or as a partial agonist on dopamine D3 and D2 receptors.RGH-188 displayed potent antipsychotic activity (0.1-0.8 mg/kg) in rodent models such as apomorphine-induced climbing, amphetamine- and phencyclidine-induced hypermotility, conditioned avoidance response. It significantly improved the learning performance of rats (0.02-0.2 mg/kg) impaired by scopolamine in a water-labyrinth learning paradigm. RGH-188 showed no EPS liability as it produced no catalepsy up to 100-fold therapeutic range.In a nonhuman primate positron emission tomography (PET) study using 11C-raclopride RGH-188 occupied striatal D2/D3 receptors in a dose dependent and saturable manner with an ED50 of 7 μg/kg iv. In healthy male subjects multiple administration of 1 mg RGH-188 resulted in over 70% D2/D3 receptor occupancy and the displacement showed correlation with RGH-188 and metabolites plasma levels.After single administration to healthy volunteers, Tmax for RGH-188 was 3-4 hours and the terminal disposition half-life was 5-6 days. Over the dose range of 0.5-2.5 mg AUC of the parent drug was approximately dose-proportional. Systemic exposure to the pharmacologically active metabolites, desmethyl- and didesmethyl-RGH-188 was 20-30% and 50-200% of that to the parent, respectively.

Pharmacokinetics of mycophenolic acid in liver transplant patients after intravenous and oral administration of mycophenolate mofetil

The bioavailability of mycophenolic acid (MPA) after oral administration of mycophenolate mofetil (MMF) has been reported to be more than 90% in healthy volunteers, and in kidney and thoracic organ transplant patients. Such information is limited in liver transplant (LTx) patients. The present study compares the pharmacokinetics of MPA after intravenous (IV) and oral administrations of MMF in LTx recipients. Pharmacokinetic parameters were calculated using WinNonlin software. A total of 12 deceased donor LTx patients initially received IV MMF and were switched to oral MMF after 2-7 days (mean, 3.3 +/- 1.7) when oral feeds were started. Multiple blood samples were drawn immediately prior to and after IV or oral MMF and the plasma concentration of MPA was measured. The mean peak plasma concentrations and the area under the plasma concentration vs. time curve (AUC) were significantly higher after IV MMF compared to oral MMF (peak plasma concentrations of 10.7 +/- 2.1 microg/mL for IV vs. 4.5 +/- 2.8 microg/mL for oral; P = 0.0001; and AUC of 28.9 +/- 7.1 microg . hr/mL for IV vs. 12.8 +/- 4.2 microg . hr/mL for oral; P = 0.0001). The oral bioavailability of MPA was 48.5 +/- 18.7%. The systemic clearance, half-life, and steady state volume of distribution of MPA were 26.9 +/- 6 L/hour, 5.5 hours, and 85 liters, respectively. The terminal disposition half-life was not significantly different between the 2 routes of administration. In conclusion, during the early postoperative period, LTx recipients have MPA exposure with oral MMF of less than half that of IV MMF. Use of IV MMF immediately post-LTx may provide an immunological advantage.

Opioid Analgesics for Persistent Pain in the Older Patient

Naturally occurring opioids have been used as analgesics for thousands of years. From these, semisynthetic and synthetic derivatives have emerged in the search for the ‘perfect’ opioid analgesic, without success. Weak opioid analgesics include codeine and propoxyphene, intermediate-strength opioid analgesics include the agonist-antagonists (e.g., pentazocine and butorphanol) and the partial agonist buprenorphine and the strong opioid analgesics include morphine, oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl and meperidine. Propoxyphene, meperidine, agonist-antagonists and partial agonists should be avoided in most elderly patients owing to their unfavorable risk–benefit profiles. The other opioids can be recommended for use in the elderly and appear to be interchangeable (in equianalgesic doses) based upon similar efficacy and tolerability profiles. The aging process alters the pharmacokinetics of nearly all opioid analgesics, mainly due to alternations in the activity of excretory pathways (liver and kidneys). The need for frequent dosing of these drugs, due to their short terminal disposition half-lives, can be largely overcome by using oral or transdermal extended-release formulations that allow dosing as infrequently as every 3 days. Opioid side effects can be anticipated and, in virtually all cases, either tolerance develops or pre-emptive therapy can prevent the emergence of or minimize the impact of the side effect (e.g., laxative therapy prevents constipation). Opioid analgesics are effective for virtually all types of pain, including neuropathic pain (where chronic opioid therapy works, while ‘as-needed’ therapy does not). This review summarizes the evidence for and against the use of individual opioid analgesics in the elderly. This, in turn, should promote the safe and effective use of the preferred opioid analgesics in this patient population.

Daptomycin: The First Approved Lipopeptide Antimicrobial

To review the literature concerning the first Food and Drug Administration-approved lipopeptide antimicrobial, daptomycin. A PUBMED search was conducted to identify pertinent English-language journal articles between 1985 and November 2003, and additional references were obtained from the bibliographies of these articles. Abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy meetings from 1985 through 2003 also were reviewed. All studies evaluating any aspect of daptomycin. Daptomycin is a semisynthetic lipopeptide, the first such antimicrobial agent to reach the marketplace. Its mechanism of action differs from that of the related agent vancomycin in that much of its effect is not because of inhibition of peptidoglycan biosynthesis, but instead is a result of alterations in cell-membrane electrical charge and transport. It exhibits a broad spectrum of activity against gram-positive aerobes and anaerobes, including methicillin-, penicillin-, aminoglycoside-, and vancomycin-resistant strains. In subjects with normal renal function, the terminal disposition half-life is about 7 to 10 hours. It is principally eliminated as unchanged drug in the urine. Available clinical trial data demonstrate efficacy in complicated skin and skin-structure infections resulting from susceptible gram-positive pathogens, but not in pneumonia. The principal adverse event of concern, although rare, is myotoxicity, manifested by muscle pain and/or weakness and elevated serum creatine phosphokinase (CPK) concentrations. The approved dosage regimen is 4 mg/kg intravenously over 30 minutes once daily for 7 days to 14 days. Studies are underway evaluating doses of up to 8 mg/kg once daily. Daptomycin, the first lipopeptide antimicrobial to be marketed, exhibits activity against multiresistant gram-positive pathogens, including linezolid- and quinupristindalfopristin-resistant strains. As such, it is a potentially valuable agent to treat infections resulting from such pathogens. To preserve its utility, it should not be used indiscriminately for infections resulting from pathogens sensitive to other antimicrobials. It is probably best used with restricted access and used only for multiresistant gram-positive pathogens where alternative agents cannot be employed. If used, careful monitoring for the signs and symptoms of myotoxicity, including obtaining weekly serum CPK levels, is mandatory. In addition, bacterial sensitivities to this agent should be prospectively monitored by national antimicrobial surveillance programs like SENTRY, TRUST, and LIBRA.

Trandolapril: A newer angiotensin-converting enzyme inhibitor

Background: Trandolapril is a newer angiontensin-converting enzyme (ACE) inhibitor that is approved by the US Food and Drug Administration for the treatment of hypertension and for use in stable patients who have evidence of left ventricular (LV) systolic dysfunction or symptoms of chronic heart failure within the first 2 days after an acute myocardial infarction (AMI). The fixed-dose combination of trandolapril and verapamil extended release (ER) is approved for the treatment of hypertension only. Objective: The purpose of this article was to review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of trandolapril as monotherapy and in fixed-dose combination with verapamil ER. Methods: Relevant studies were identified through a MEDLINE/PubMed search of the English-language literature published between January 1983 and August 2002 and a review of the bibliographies of identified articles. Results: Trandolapril has a sufficient duration of inhibition of plasma ACE activity to allow once-daily dosing. It is converted by esterases to the active trandolaprilat metabolite, with mean terminal disposition half-lives of <1 and ∼75 hours for the prodrug and metabolite, respectively. In comparative trials in the management of hypertension, trandolapril 1 to 4 mg/d was statistically indistinguishable from or superior to captopril 100 mg/d, enalapril 10 or 20 mg/d, hydrochlorothiazide (HCTZ) 25 mg/d, nifedipine ER 30 or 40 mg/d, nitrendipine 20 mg/d, perindopril 4 mg/d, and verapamil ER 120 to 240 mg/d. In the Trandolapril Cardiac Evaluation, trandolapril also significantly reduced all-cause mortality, cardiovascular mortality, sudden death, and progression to severe chronic heart failure in patients with evidence of LV systolic dysfunction after AMI. In comparative trials in the management of hypertension, the combination of trandolapril 1 or 2 mg/d and verapamil ER 180 mg/d was statistically indistinguishable from or superior to the combinations of atenolol 50 or 100 mg/d plus chlorthalidone 12.5 or 25 mg/d, captopril 50 mg/d plus HCTZ 25 mg/d, lisinopril 20 mg/d plus HCTZ 12.5 mg/d, and metoprolol 100 mg/d plus HCTZ 12.5 mg/d. The most common adverse effects of trandolapril monotherapy in clinical trials of ≤1 year's duration included cough, dizziness, and diarrhea (frequency ≤1.9%). The most common adverse effects of trandolapril/verapamil ER therapy in clinical trials of ≤1 year's duration included first-degree atrioventricular block, bradycardia, constipation, cough, diarrhea, dizziness, fatigue, and dyspnea (frequency ≤4.6%). Based on the literature search, there are no published pharmacoeconomic evaluations of trandolapril alone or combined with verapamil ER in the US health care setting. Conclusions: Based on the literature, trandolapril is a well-tolerated and effective antihypertensive agent, whether used alone or in combination with verapamil ER. These products may be valuable in patients with LV systolic dysfunction after AMI, although the combination product is approved for the management of hypertension only.

Lung deposition and pharmacokinetics of cyclosporine after aerosolization in lung transplant patients.

Aerosolized cyclosporine (aCsA) has proven to be an effective therapy for refractory acute and chronic rejection in lung transplant (LTx) patients. The objective of this study is to evaluate the lung deposition and systemic absorption of aCsA after aerosolized cyclosporine administration in LTx patients in the immediate postoperative period. Cyclosporine (CsA) was administered intravenously (1.0 mg/kg) to eight LTx patients, and multiple blood samples were collected over 24 h. At least 24 h later, aCsA (300 mg in propylene glycol) was administered to the same patients using nebulization and multiple blood samples were obtained again. Five patients had an additional inhalational gamma scintigraphy study with aCsA and 99MTc-labeled albumin to measure drug deposition. Peak blood concentrations of CsA after aerosol administration ranged from 119-402 ng/ml, and concentrations at 24 h ranged from 9-48 ng/ml. The rate of decline in drug concentration in blood in the apparent elimination phase was notably slower after administration of aCsA than after IV infusion. Terminal disposition half life (t 1/2 lambda(z)) values ranged from 4.1-9.9 h (mean 6.5 h) following IV administration and from 23.1 to 65.2 h (mean 40.7 h) following pulmonary administration, suggesting that drug absorption occurred throughout the 24-h sampling period following pulmonary administration. Deconvolution analysis indicated biphasic absorption of CsA from the lung in all patients, characterized by rapid initial absorption (absorption half-life 0.73 +/- 0.38 h) over the first 4 to 6 h followed by slower, sustained absorption throughout the remainder of the sampling period (absorption half-life 16.2 +/- 13.2 h). The absolute bioavailability of CsA after aerosol administration ranged from 5.4-11.2% (mean 8.2%) of the dose placed in the nebulizer. The total dose delivered to the lung estimated from scintigraphy ranged from 17.8-39.3 mg, and was in approximate agreement with the amount of drug absorbed, estimated using deconvolution. Essentially all drug deposited in the lungs was systemically absorbed. This study documents that cyclosporine can be effectively delivered by aerosolization to the lung of transplant patients in the early postoperative period. Part of the cyclosporine deposited in the lung is absorbed rapidly into systemic circulation and a portion is absorbed slowly but completely over a prolonged period.

Clinical Pharmacokinetics of Drugs Used to Treat Urge Incontinence

Urge incontinence (also known as overactive bladder) is a common form of urinary incontinence, occurring alone or as a component of mixed urinary incontinence, frequently together with stress incontinence. Because of the pathophysiology of urge incontinence, anticholinergic/antispasmodic agents form the cornerstone of therapy. Unfortunately, the pharmacological activity of these agents is not limited to the urinary tract, leading to systemic adverse effects that often promote nonadherence. Although the pharmacokinetics of flavoxate, propantheline, scopolamine, imipramine/desipramine, trospium chloride and propiverine are also reviewed here, only for oxybutynin and tolterodine are there adequate efficacy/tolerability data to support their use in urge incontinence. Oxybutynin is poorly absorbed orally (2-11% for the immediate-release tablet formulation). Controlled-release oral formulations significantly prolong the time to peak plasma concentration and reduce the degree of fluctuation around the average concentration. Significant absorption occurs after intravesical (bladder) and transdermal administration, although concentrations of the active N-desethyl metabolite are lower after transdermal compared with oral administration, possibly improving tolerability. Food has been found to significantly affect the absorption of one of the controlled-release formulations of oxybutynin, enhancing the rate of drug release. Oxybutynin is extensively metabolised, principally via N-demethylation mediated by the cytochrome P450 (CYP) 3A isozyme. The pharmacokinetics of tolterodine are dependent in large part on the pharmacogenomics of the CYP2D6 and 3A4 isozymes. In an unselected population, oral bioavailability of tolterodine ranges from 10% to 74% (mean 33%) whereas in CYP2D6 extensive metabolisers and poor metabolisers mean bioavailabilities are 26% and 91%, respectively. Tolterodine is metabolised via CYP2D6 to the active metabolite 5-hydroxymethyl-tolterodine and via CYP3A to N-dealkylated metabolites. Urinary excretion of parent compound plays a minor role in drug disposition. Drug effect is based upon the unbound concentration of the so-called 'active moiety' (sum of tolterodine + 5-hydroxymethyl-tolterodine). Terminal disposition half-lives of tolterodine and 5-hydroxymethyl-tolterodine (in CYP2D6 extensive metabolisers) are 2-3 and 3-4 hours, respectively. Coadministration of antacid essentially converts the extended-release formulation into an immediate-release formulation. Knowledge of the pharmacokinetics of these agents may improve the treatment of urge incontinence by allowing the identification of individuals at high risk for toxicity with 'usual' dosages. In addition, the use of alternative formulations (controlled-release oral, transdermal) may also facilitate adherence, not only by reducing the frequency of drug administration but also by enhancing tolerability by altering the proportions of parent compound and active metabolite in the blood.

Cefdinir: An advanced-generation, broad-spectrum oral cephalosporin

Background: Cefdinir is an advanced-generation, broad-spectrum cephalosporin antimicrobial agent that has been approved for the treatment of community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, acute maxillary sinusitis, pharyngitis/tonsillitis, acute bacterial otitis media, and uncomplicated skin and skin-structure infections in adult and pediatric patients. Objective: The purpose of this article was to review the in vitro antimicrobial activity, pharmacokinetics, clinical efficacy, safety, and potential role of cefdinir. Methods: Studies were identified by a MEDLINE search (January 1983–September 2001) of the English-language medical literature, a review of identified articles and their bibliographies, and a review of data on file with the manufacturer. Clinical efficacy data were selected from all published trials mentioning cefdinir. Information concerning in vitro susceptibility, safety, chemistry, and the pharmacokinetic profile of cefdinir also was reviewed. Results: Cefdinir has a broad spectrum of activity against many gram-negative and gram-positive aerobic organisms, including Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis. Cefdinir is stable to hydrolysis by 13 of the common beta-lactamases. It is rapidly absorbed from the gastrointestinal tract (mean time to peak plasma concentration, 3 hours) and is almost entirely eliminated via renal clearance of unchanged drug. The terminal disposition half-life of cefdinir is ∼1.5 hours. Efficacy has been demonstrated in 19 clinical trials in adults and children with upper and lower respiratory tract infections (eg, pharyngitis, sinusitis, acute otitis media, acute bronchitis, acute bacterial exacerbation of chronic bronchitis, community-acquired pneumonia), and skin and skin-structure infections. The adverse-event profile is similar to that of comparator agents, although in 4 adult and adolescent studies and 1 adult study, diarrhea occurred significantly more frequently in cefdinir recipients than in recipients of penicillin V, cephalexin, cefaclor, and cefprozil. Conclusions: Cefdinir is an alternative to other antimicrobial agents and can be dosed once or twice daily for the treatment of upper and lower respiratory tract infections and skin and skin-structure infections. Similar to other oral expanded-spectrum cephalosporins, cefdinir has activity against common pathogens of the respiratory tract and skin and is stable in the presence of selected beta-lactamases. The clinical choice of an oral expanded-spectrum cephalosporin will be based on patient acceptance, frequency of administration, and cost.

Review of cefditoren, an advanced-generation, broad-spectrum oral cephalosporin

Background: Cefditoren is an advanced-generation, broad-spectrum cephalosporin antibiotic approved for the treatment of acute bacterial exacerbation of chronic bronchitis (AECB), group A beta-hemolytic streptococcal pharyngotonsillitis, and uncomplicated skin/skin structure infections in adult and adolescent patients. Objective: This article briefly reviews the chemistry, antimicrobial activity, pharmacokinetics, efficacy, and safety of cefditoren. Methods: Literature was identified by a MEDLINE search (January 1985 to October 2001) of the medical literature, review of the English-language literature, reference lists within these articles, as well as data presented at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Results: Cefditoren has a broad spectrum of activity against many gram-negative and gram-positive aerobes, including Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis. Cefditoren is stable to hydrolysis by many common beta-lactamases. Cefditoren is rapidly absorbed (time to peak plasma concentration, ∼2–3 hours) from the gastrointestinal tract and is almost completely eliminated via renal clearance of unchanged drug. The terminal disposition half-life of the compound is ∼0.8 to 1.3 hours. Conclusions: Cefditoren is effective in the management of AECB (in regimens of 400 mg twice daily for 10 days) and acute maxillary sinusitis, pharyngotonsillitis due to S pyogenes, and uncomplicated skin/skin structure infections (in regimens of 200 mg twice daily for 10 days). Cefditoren possesses broad activity against common pathogens of the respiratory tract and skin and is stable in the presence of numerous beta-lactamases. Its pharmacokinetic properties, in conjunction with in vitro susceptibility data, document the feasibility of twice-daily dosing.

Cefdinir: an expanded-spectrum oral cephalosporin.

To review the antimicrobial activity, pharmacokinetics, clinical efficacy, and tolerability of cefdinir, an expanded-spectrum oral cephalosporin. Literature was identified by a MEDLINE search (January 1983-November 1999) of the medical literature, review of English-language literature and bibliographies of these articles, and product information. Clinical efficacy data were selected from all published trials mentioning cefdinir. Additional information concerning in vitro susceptibility, safety, chemistry, and pharmacokinetic profile of cefdinir was also reviewed. Cefdinir, an oral expanded-spectrum cephalosporin, has a broad spectrum of activity against many gram-negative and -positive aerobic organisms, including Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis. Cefdinir is stable to hydrolysis by many common beta-lactamases. Cefdinir is rapidly absorbed from the gastrointestinal tract and is primarily eliminated via renal clearance of unchanged drug. The terminal disposition half-life of cefdinir is approximately 1.5 hours. Efficacy has been demonstrated in a number of clinical trials in adults and children with upper and lower respiratory tract infections (e.g., pharyngitis, sinusitis, acute otitis media, acute bronchitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia) and skin and skin-structure infections. The adverse event profile is similar to that of comparator agents. Cefdinir is a second-line alternative to first-line antimicrobial agents, with convenient once- or twice-daily dosing in the treatment of upper and lower respiratory tract infections and skin and skin-structure infections. Similar to other oral expanded-spectrum cephalosporins, cefdinir has activity against common pathogens of the respiratory tract and skin and is stable in the presence of many beta-lactamases. The clinical choice of an oral expanded-spectrum cephalosporin will be based on patient acceptance, frequency of administration, and cost.

Tolterodine, a new antimuscarinic drug for treatment of bladder overactivity.

Tolterodine is a nonsubtype selective antimuscarinic agent recently approved as therapy in patients with overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence. It acts by muscarinic receptor blockade in the bladder wall and detrusor muscle. Despite short terminal disposition half-lives of 2-3 and 3-4 hours for tolterodine and its active 5-hydroxy metabolite, respectively, twice/day dosing is effective due to the drug's prolonged pharmacodynamic effects. Dosage adjustment is recommended in the presence of hepatic impairment and during concurrent therapy with drugs that inhibit cytochrome P450 2D6 and 3A4 isozymes. Tolterodine significantly reduces clinically relevant end points such as number of micturitions and number of incontinence episodes/day. In general, it is superior to placebo and equivalent to oxybutynin in this regard. As might be expected from its pharmacologic profile, the principal adverse effects of the drug are anticholinergic. In clinical trials, tolterodine was tolerated significantly better than oxybutynin. Its relative merits as a first- or second-line agent for patients intolerant of oxybutynin are unclear. Until pharmacoeconomic analyses are conducted that clearly justify use of this more expensive agent, tolterodine is perhaps best reserved for patients who are intolerant of or fail oxybutynin therapy.

Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson's disease.

Tolcapone is a selective peripheral and central catechol-O-methyltransferase (COMT) inhibitor recently approved as adjunctive therapy in patients with idiopathic Parkinson's disease who are already being treated with a levodopa-peripheral dopa decarboxylase inhibitor (DDI) combination. Tolcapone potentiates and prolongs the effect of levodopa in the central nervous system (CNS) by enhancing levodopa's delivery to the CNS and slowing dopamine's central metabolism. A short terminal disposition half-life of 2 hours mandates dosing 3 times/day. Dosage adjustment is generally unnecessary in the presence of mild to moderate renal and hepatic impairment. Coadministration of tolcapone with levodopa-DDI results in significant amelioration of the wearing-off and on-off phenomena and frequently allows significant levodopa dosage reduction. In patients with stable disease, tolcapone improves "on" time. As might be expected from its potentiation of levodopa effects, dopaminergic side effects are prominent with this agent. Although the main objective of drug treatment in Parkinson's disease remains clinical improvement with an optimum dose and frequency of levodopa administration, tolcapone may prove a useful adjunct to such therapy, especially in the presence of the wearing-off and on-off phenomena. The relative merits of this agent vis-a-vis dopamine receptor agonists are somewhat unclear at present. However, recent guidelines from the American Academy of Neurology suggest that a COMT inhibitor be added to levodopa-dopamine agonist therapy in patients with advanced disease.

Disposition of the Selective α1A-Adrenoceptor Antagonist Tamsulosin in Humans: Comparison with Data from Interspecies Scaling

□ Tamsulosin•HCl is an α1A-adrenoceptor antagonist that is mainly eliminated by metabolism in animals and humans and is highly bound to α1-acid glycoprotein in blood plasma. The disposition of the compound (0.4mg as modified-release granules in a capsule) was determined in male volunteers, using intravenous (iv) infusion of tamsulosin·HCl (0.125mg over 4h) as reference treatment for the assessment of absolute oral bioavailability. Disposition parameters of iv tamsulosin in humans was compared with data predicted from animal data by interspecies scaling techniques. Levels after iv dosing in humans showed a biexponential decline, with mean half-lives (±SD) of 1.2±0.6 and 6.8±3.5h, respectively. The mean systemic clearance (±SD) was low (viz., 48±24mL/min). The mean volume of distribution (±SD) was rather small (21±6L), and was estimated at 16±4L in the steady state. The mean absolute oral bioavailability (±SD) was approximated at 100±19%. Systemic clearance in humans was poorly predictable from a logarithmic clearance versus body weight relation of rat, rabbit, and dog data. The prediction improved dramatically (accuracy 213%) when scaling was done with systemic clearance values of unbound drug, and it improved further (accuracy 59%) with the product of unbound clearance and maximum life-span potential. Also, the prediction of volume of distribution improved dramatically (accuracy 81%) after correction for differences in extent of protein binding between species. The terminal disposition half-life of 7.0h, as predicted after integrating maximum lifespan potential and protein binding in scaling of clearance, was very close to the value of 6.8h established experimentally in humans. The present results with tamsulosin underline the importance of correction for extent of protein binding in allometric scaling of clearance and distribution volume.