Renal impairment clinical trials

CrCl greater than or equal to 30 to less than 50 mL/minute) and severe (CrCl less than 30 mL/minute) renal impairment respectively. Renal function monitoring is recommended prior to initiation and periodically thereafter. Adverse events in clinical trials included nasopharyngitis (5.2%), upper respiratory tract infection (6.3%), and headache (5.1%). Currently, no significant drug interactions are known. 

Clinical trials may need to be conducted in certain study subject groups that are often either not included or are poorly represented in standard clinical development programmes. These include children, the elderly and those with a quantified degree of renal or hepatic impairment and ethnic minorities. Moreover, it may be necessary to consider specific studies in women of childbearing age for drugs other than those specifically designed for them, such as... 

Gl Gl symptoms are the most common reactions to miglitol. The incidence of diarrhea and abdominal pain tend to diminish considerably with continued treatment. Renal function impairment Plasma concentrations of miglitol in renally impaired volunteers were proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine more than 2 mg/dL) have not been conducted. Treatment of these patients with miglitol is not recommended. 

Common side effects reported in clinical trials include nausea, vomiting, diarrhea, anorexia, weight loss, dizziness, abdominal pain, and tremor. Most side effects tend to be dose related and may be decreased with a slow titration schedule of 4 mg twice daily every 4 weeks. Dosing should be done cautiously in patients with moderate renal or hepatic impairment, and galantamine should be avoided in those with severe impairment. 

Maximal plasma concentrations occur 2 to 3 hours after oral administration of reboxetine (178). Reboxetine has linear pharmacokinetics over its clinically relevant dosing range and a half-life of approximately 12 hours. For this latter reason, a twice a day, equally divided dosing schedule was used during clinical trial development. Its clearance is reduced and half-life becomes longer as a function of advanced age (mean = 81 years of age) and renal and hepatic impairment ( 178, 322, 323). Reboxetine is principally metabolized by CYP 3A3/4 such that its dose should be reduced when used in combination with drugs that are substantial inhibitors of CYP (e.g., certain azole antifungals, certain macrolide antibiotics). Reboxetine itself, however, does not cause detectable inhibition of CYP 3A3/4 based on formal in vivo pharmacokinetic interaction studies as well as its own linear pharmacokinetics. 

Toxicities include elevation of liver enzymes with some risk of liver damage, renal impairment, and teratogenic effects. A low frequency of cardiovascular effects (angina, tachycardia) was reported in clinical trials of leflunomide. 

Does the CRO have access to the patient population needed for the trial For example, some CROs maintain specific patient pools, such as patients with hepatic impairment or renal impairment, often needed for clinical pharmacology studies. 

Pancytopenia is a rare but potentially fatal complication, and numerous reports have been published. The characteristics and incidence of pancytopenia have been carefully re-evaluated from case reports and clinical trials published from 1980 to 1995 (38). Of 70 reported cases, 12 patients died (17%). Impaired renal function was the most important contributing factor (54%), particularly in fatal cases (10/12). Other important susceptibility factors included advanced age (over 65 years), hypoalbuminemia, concurrent infection, and/or concomitant multiple medications (particularly co-trimoxazole). The mean cumulative dosage was 675 (10-4800) mg, and the minimal cumulative methotrexate dose leading to fatal pancytopenia was 10 mg. This confirms that pancytopenia can occur at any time during treatment, even in the absence of known susceptibility factors. Bone marrow biopsy showed megaloblastosis and hypocellularity. Eosinophilia and increased mean corpuscular volume were rarely observed. In an overall review of five long-term prospective studies (511 patients), the calculated incidence of methotrexate-induced pancytopenia was 1.4%. Although severe myelo-suppression sometimes required folinic acid, there are as yet no data to determine whether prophylactic folate supplementation can reduce the incidence of pancytopenia. 

In clinical trials the safety profile of aztreonam was similar to or better than that of other more conventional beta-lactam antibiotics, in adult patients with both normal renal function (3,4) and impaired renal function (5). These findings have been confirmed in children (6). 

Harland SJ, Newell DR, SiddikZH, Chadwick R,Calvert AH, Harrap KR. Pharmacokinetics of cis-diammine-1,1-cyclobutane dicarboxylate platinum[ll] in patients with normal and impaired renal function. Cancer Res. 1984 Apr 44[4] 1693-7 Koeller JM,Trump DE,Tutsch KD, Earhart RH, DavisTE,Tormey DC. Phase I clinical trial and pharmacokinetics of carboplatin [NSC 241240] by single monthly 30-minute infusion. Cancer. 1986 Jan 15 57[2] 222-5... 

Although differences in the incidence of renal adverse events between bisphosphonates have been reported from clinical trials, the reasons for these observations remain unknown but may be specific to a particular drug, dosing regimen, or prunary tumour type. Although more common in patients with pre-existing renal impairment, nephrotoxicity is not exclusive to this patient population. Clearly, further comparative chnical trials would be needed to directly compare the renal safety profiles of different i.v. bisphosphonates. 

Clonazepam 0.5 mg t.i.d. 2 mg t.i.d. 1% 100% 100% 100% Although no dose reduction is recommended, the drug has not been studied in patients with renal impairment recommendations based on known drug characteristics not clinical trials data NC NC NC... 

Once-daily administration of 2.5 mg of indapamide has shown the drug to be a safe and effective agent to use in lowering blood pressure of hypertensive patients with normal renal function as well as patients with various degrees of renal impairment and those undergoing long-term maintenance hemodialysis (4). Results from clinical trials indicate that indapamide effectively reduces arterial blood pressure in approximately two-thirds of patients with mild to moderate hypertension, is well tolerated and does not induce biochemical abnormalities that constitute cardiovascular risk factors (3). Indapamide has also been shown to produce a clinically significant decrease in edema (5) as well as a reduction in total peripheral resistance (6). 

When ill persons are offered money over and above expenses to enter a clinical trial of a new drug therapy, the possibility of coercion exists. The reasoning is that if the patient is poor, they might not be able to afford the therapy without entering the trial. Contrast this experience with renally impaired volunteers recruited for a pharmacokinetic study of an antibiotic. Renal failure is not the target of therapy. The subjects receive no therapeutic benefit from participating and are paid as volunteers. 

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