Pitfalls of pharmacokinetic dosage guidelines in renal insufficiency

As the renal elimination of most drugs is closely correlated with the endogenous creatinine clearance, it is possible to use this parameter of kidney function to adjust drug dosage in renal failure. However, this simple procedure neglects possible changes in the volume of distribution, plasma protein binding, drug metabolism, intestinal absorption, and pharmacodynamics in renal insufficiency, as well as the occurrence of biologically active drug metabolites. Because of these uncertainties in critical cases the validity of the dosage calculated using the creatinine clearance should be checked by clinical surveillance and measurements of drug blood concentrations. Further, pharmacokinetic dosage guidelines based on the individual creatinine clearance may not be applicable to diuretics and drugs which have markedly differing kinetics of pharmacodynamic effects and blood levels.     

Cimetidine dosage regimen for patients with renal failure and for geriatric patients

Summary Using a recently developed computer program based on a correlation between methods to predict the elimination half-life and apparent volume of distribution of cimetidine and actual data from patients, ideal dosage regimens were generated for patients with renal impairment and for geriatric patients, together with the corresponding maximum and minimum steady state concentrations. Using the ideal dosage regimens, practical regimens with feasible dosing intervals of 6, 8 and 12 h were computed, which should result in therapeutic concentrations of 0.4 to 1.3 µg/ml. For uraemic patients and geriatric patients above the age of 75 years it would be desirable to have an additional oral 100 mg dosage form.     

Nomogram for drug dosage adjustment in patients with renal failure

A nomogram is presented for the rapid determination of the dosage adjustment factor for drugs eliminated in part by the kidneys in patients with reduced renal function. This nomogram method is based on knowledge of the fraction of a dose of the drug of interest eliminated by the kidneys in subjects with normal renal function and an estimation of the renal function of the patient in question. It assumes that there is no reduction in the liver metabolism of the drug in patients with reduced renal function. The dosage adjustment factor thus derived can be used to change the dosage regimen of the drug in patients with reduced renal function.     

A concept for pharmacokinetic-pharmacodynamic dosage adjustment in renal impairment: the case of aminoglycosides

BACKGROUND: For patients with impaired renal function, dosage adjustment is necessary for many drugs. Adjustment with respect only to pharmacokinetic parameters may be insufficient. OBJECTIVE: To apply the theory of pharmacokinetics and pharmacodynamics to derive a mathematical model that links the concentration-time course and the clinical response by means of the pharmacokinetic-pharmacodynamic parameter 'area under the effect-time curve' (AUETC), and to use this analysis and clinical data for aminoglycosides to calculate dosage adjustments in renal impairment. METHODS: Model parameters were estimated for the antimicrobial and nephrotoxic effects of aminoglycosides on the basis of data from the literature. Effect parameters were calculated for various degrees of impaired renal function. RESULTS: Use of the model parameters gave a high correlation between the predicted and the observed (literature) values for antimicrobial efficacy and nephrotoxicity. When calculating dosage adjustments in renal impairment, it was possible to hold only one effect (antimicrobial or nephrotoxic) constant by dosage adjustment, whereas the other changed unfavourably. This was explained by differences between the pharmacodynamic parameters for each effect. For high antimicrobial efficacy, a target peak concentration of 9 mg/L (for gentamicin) should be obtained every 48 hours in advanced renal impairment. For low nephrotoxicity, the peak concentration should not exceed 3 mg/L. CONCLUSIONS: The parameter AUETC could be a useful pharmacokinetic-pharmacodynamic surrogate marker for dosage adjustment in renal impairment. Using the AUETC method, the beneficial effect can be balanced against the adverse effect.     

Aortocoronary bypass surgery and chronic renal failure: case report.

A successful case of aortocoronary bypass operation in a patient with chronic renal failure managed by home haemodialysis and being considered for renal transplantation is described.     

Aminoglycoside dosage adjustment in renal failure: A hand-held calculator program

Summary Several problems occur when devising dosage guidelines for aminoglycoside antibiotics in patients with renal failure. To rationally address these problems, dosage guidelines require several steps involving complex calculations, use of graphic charts and/or use of sophisticated computer systems. We describe a practical program for modifying doses of aminoglycosides using a programmable hand-held calculator; this program is based both on pharmacokinetic theory and on applicability to varied clinical settings. The program compiles a series of equations to provide recommended doses, dosing intervals and predictions of serum concentrations of aminoglycosides at various times after a dose. It is hoped that patient care can be improved by using this simple, convenient and low-cost approach which retains efficiency and accuracy as a bed side method of dosage adjustment for aminoglycosides.     

Acute renal failure and polymyositis: case report

Acute renal failure is a rare complication of acute polymyositis. We describe the first case noted in New Zealand and demonstrate the occasional serious nature of this disease and the role of corticosteroids in its management.     

Pharmacokinetic dosage guidelines for elderly subjects

Ageing is associated with a decline in drug elimination; hence, using the same doses as in younger adults may result in higher plasma drug concentrations and toxicity. Two approaches are available for dose correction to account for decreased drug elimination. One procedure is based on the extrarenal elimination fraction (Q(0)) and the age-dependent changes in creatinine clearance; the other uses the decline in total drug clearance (CL). Mean values of Q(0) and CL in young and old people are reported for many drugs in the literature and are summarised in this article. Although the pharmacokinetic techniques for dose adjustment in the elderly are useful, they provide only an average dose correction and neglect age-dependent changes in drug bio-availability, plasma protein binding, the fate of active metabolites, and altered sensitivity to drugs. To account for pharmacodynamic changes in old age, clinical and/or biochemical targets should be defined as therapeutic goals. Drugs whose effects cannot be monitored in these terms should be avoided in elderly individuals.     

Quinine dosage in severe malaria with renal failure necessitating haemodialysis

Summary For therapy of severe malaria with renal failure, a 2/3 reduction in the usual intravenous dose of quinine is recommended (600 mg per 24 h instead of 600 mg per 8 h). Two patients with severe malaria and renal failure requiring dialysis have been treated.The half-life was not prolonged (15 h). Quinine proved to be nondialysable. It was shown that this dose of quinine tended to lead to a low level in blood (under 10 mg·l^–1).A normal dose of quinine (2×15 mg/kg per day) is therefore recommended for malaria therapy, even in cases with renal failure requiring haemodialysis, in order to attain the desired plasma level (5 to 15 mg·l^–1).     

Enoxaparin dosage adjustment in patients with severe renal failure: antifactor xa concentrations and safety

STUDY OBJECTIVE: To evaluate the safety and efficacy, by measuring antifactor Xa levels, of enoxaparin 1 mg/kg subcutaneously once every 24 hours in patients with severe renal failure. DESIGN: Prospective study. SETTING: Emergency, internal medicine, geriatrics, and cardiology departments of a medical center in Israel. PATIENTS: Nineteen patients with stage 4 or 5 chronic kidney disease who required full anticoagulation. INTERVENTION: Patients received enoxaparin 1 mg/kg subcutaneously every 24 hours for 2 or more days, as determined by a treating physician. MEASUREMENTS AND MAIN RESULTS: Data on patients' demographic and clinical characteristics were collected. Blood samples for peak and trough antifactor Xa levels were obtained during the enoxaparin treatment period. Of the 19 study patients, 14 (74%) had peak antifactor Xa levels within the recommended range for full anticoagulation of 0.5-1.0 U/ml after their first enoxaparin dose; no concentration exceeded 1.0 U/ml. The mean peak antifactor Xa level was not significantly different after the first enoxaparin dose compared with the second and third doses. The mean +/- SD trough antifactor Xa level, thought to be an indicator of drug accumulation, was 0.12 +/- 0.12 U/ml; its clinical significance and target range are still unknown. No major bleeding events were noted. CONCLUSION: Enoxaparin 1 mg/kg once every 24 hours in patients with stage 4 or 5 chronic kidney disease who required full anticoagulation was safe, and this dose did not exceed recommended concentrations. The significance of enoxaparin trough levels remains unclear and should be investigated in future studies. Other dosing regimens of enoxaparin for specific patient populations should also be assessed for safety and efficacy.     

Congestive heart failure: guidelines for the primary care physician

Heart failure is a common medical condition affecting nearly 5 million people each year in the United States, of whom 500,000 are newly diagnosed. The impact of this disease on society and the health care system is immense. Inpatient and outpatient costs are approximately $40 billion annually, almost $500 million of which is spent on heart failure medications alone. Beyond the problem of financial costs, however, it is imperative for us as health care professionals to improve our ability to prevent disease progression, decrease morbidity and mortality, and optimize patients quality of life. The use of a broad spectrum of treatments is reviewed in the context of a patient case study. Primary data justifying the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, digoxin, as well as beta blockers and spironolactone, is reviewed, with special reference to the stage of heart failure.     

Intravenous immunoglobulin-associated acute renal failure: case series and literature review

Intravenous immunoglobulin (IVIg) is widely used in the treatment of immunodeficient and autoimmune hematologic, neurologic, rheumatologic, and cutaneous disorders. The major adverse effects of IVIg infusions are pain (chest, hip, joint, and back), fever, chills, and fatigue. These effects are related to the rate of the infusion and may be attenuated by slowing the rate. The addition of sugar excipients to IVIg formulations has reduced the frequency and severity of these adverse effects but may increase the frequency of acute renal failure. We describe four patients who experienced acute renal failure after IVIg administration. In each patient, the IVIg formulation contained significant amounts of sucrose, and the patient's renal function returned to baseline after discontinuation of therapy. Clinicians should be familiar with patients who are at increased risk of acute renal failure secondary to IVIg administration. Furthermore, IVIg preparations that contain high amounts of sucrose should be administered with caution in these high-risk patients.