Pharmacokinetic interactions with calcium channel antagonists (Part II).

Since calcium channel antagonists are a diverse class of drugs frequently administered in combination with other agents, the potential for clinically significant pharmacokinetic drug interactions exists. These interactions occur most frequently via altered hepatic blood flow and impaired hepatic enzyme activity. Part I of the article, which appeared in the previous issue of the Journal, dealt with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs. Part II examines interactions with cyclosporin, anaesthetics, carbamazepine and cardiovascular agents.

Pharmacokinetic interactions with calcium channel antagonists (Part I).

Calcium channel antagonists are a diverse class of drugs widely used in combination with other therapeutic agents. The potential exists for many clinically significant pharmacokinetic interactions between these and other concurrently administered drugs. The mechanisms of calcium channel antagonist-induced changes in drug metabolism include altered hepatic blood flow and impaired hepatic enzyme metabolising activity. Increases in serum concentrations and/or reductions in clearance have been reported for several drugs used with a number of calcium channel antagonists. A number of reports and studies of calcium channel antagonist interactions have yielded contradictory results and the clinical significance of pharmacokinetic changes seen with these agents is ill-defined. The first part of this article deals with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs.

Cyclosporine dose reduction by ketoconazole administration in renal transplant recipients.

Cyclosporine metabolism occurs in the liver via hepatic cytochrome P-450 microsomal enzymes. Ketoconazole, an imidazole derivative, has been shown to inhibit the cytochrome P-450 enzyme system. Thirty-six renal transplant recipients receiving cyclosporine as part of a triple immunosuppressive drug regimen were started on 200 mg/day of oral ketoconazole. The dose of cyclosporine was reduced by 70% at the start of ketoconazole; this dose reduction was based on our previous experience with concomitant cyclosporine-ketoconazole therapy. Ketoconazole was started in patients who had been on cyclosporine for between 10 days and 74 months. The mean cyclosporine dose was 420 mg/day (5.9 mg/kg/day) before starting ketoconazole and 66 mg/day (0.9 mg/kg/day) one year after the addition of ketoconazole; this represents a cyclosporine dose reduction of 84.7% (P less than 0.0001). The mean trough whole-blood cyclosporine concentrations measured by HPLC, were 130 ng/mL preketoconazole and 149 ng/mL after 1 year of combination therapy. Mean serum creatinine and BUN levels were unchanged before and during ketoconazole administration, and no changes in liver function tests were noted. Cyclosporine pharmacokinetics were performed before and after at least three weeks of ketoconazole. Hourly whole-blood samples were measured by HPLC (parent cyclosporine only) and TDX (parent + metabolites). Combination therapy resulted in decreases in the maximum blood concentration and the steady-state volume of distribution divided by the fractional absorption, and increases in mean residence time and the parent-to-parent plus metabolite ratio (calculated by dividing the HPLC by the TDX value). The addition of ketoconazole to cyclosporine-treated patients resulted in a significant inhibition of cyclosporine metabolism and decrease in the dosage. There was minimal nephrotoxicity, and only four rejection episodes occurred on combined therapy. The concomitant administration of the two drugs was well tolerated, and there was no deleterious effect on the immunosuppressive activity of cyclosporine. This drug interaction provides a significant reduction in the costs associated with organ transplantation.

Effects of controlled liver injury and ethanol pretreatment on monoethylglycine xylidide formation in the rat.

Measuring the monoethylglycine xylidide (MEGX) serum level 15-30 min after intravenous administration of lidocaine has been shown to be an accurate predictor of early success in liver transplants. This study evaluates the changes in the MEGX formation test associated with changes in liver mass and ethanol pretreatment in a rat model. Mean MEGX levels were significantly higher for the sham-operated group versus each of the partially hepatectomized groups at 15, 30, and 45 min after injection. No differences between mean MEGX levels for either of the surgically treated groups could be distinguished. Ethanol pretreatment and body weight had no effect on MEGX levels at any of the time points tested in this model.

Critical ketoconazole dosage range for ciclosporin clearance inhibition in the dog.

Ciclosporin (CsA) is metabolized exclusively by the hepatic cytochrome P-450 mixed function oxidase system. Ketoconazole (KC) is a potent inhibitor of this enzyme system. CsA was administered alone and in combination with five different doses of KC (1.25, 2.5, 5.0, 10.0, 20.0 mg/kg/day) under steady-state conditions to 7 adult mongrel dogs. KC produced a highly significant (p = 0.0001), dose-dependent decrease in CsA total body clearance [Cl(T)]. The critical KC dosage range for this to occur was found to be between 2.5 and 10 mg/kg/day. The reduction of CsA CL(T) was insignificant (p greater than 0.05) at a KC dose of less than 2.5 mg/kg/day, and the 92% reduction observed using 20 mg/kg/day KC was not significantly greater than the 85% reduction occurring after only 10 mg/kg/day KC (p greater than 0.05). The dose of concomitant KC was also highly correlated with a reduction in the whole blood CsA parent/parent + metabolite ratio as determined using high-performance liquid chromatography and polyclonal fluorescent polarization immunoassay for CsA measurement (r = 0.998, p less than 0.0001). The absolute oral bioavailability of CsA as well as the time required to reach its maximum concentration in the blood following oral administration did not change significantly over the course of the study (p greater than 0.05). We conclude from these new observations that the KC-induced decrease in CsA Cl(T) in the dog in vivo is dose-dependent and maximized within the KC dosage range of 2.5-10 mg/kg/day. The effect does not appear to involve a decrease in the rate of CsA oral absorption, and may be compensated for by an appropriate reduction in the concomitantly administered dose of CsA.

Ancrod causes rapid thrombolysis in patients with acute stroke.

Clot lysis is desirable in patients with thrombi in arteries and arterioles by a safe rapidly-acting thrombolytic agent. Ancrod cleaves fibrinogen; the resulting circulating ancrod-fibrin stimulates fibrinolysis. Ancrod action and effect were studied in 20 patients with acute developing stroke in a double-blind, placebo-controlled study. Patients were randomly assigned to one of two treatment groups, and received either normal saline or ancrod 0.5 mu/kg in normal saline administered as a constant-rate intravenous infusion over 6 hours. Subsequent doses of ancrod (or saline placebo) were determined daily thereafter for a total treatment period of 7 days. Neither bleeding nor re-thrombosis occurred within the 90 day follow-up period. That ancrod acted rapidly was shown by a significant decrease in functional plasminogen activator inhibitor (PA-I) within 60 minutes, and by significant elevations of fibrin(ogen) degradation products (FDP) and D-dimer within 3 and 4 hours. The biological effect of fibrinolysis in ancrod infused patients was demonstrated by a greater improvement in stroke score when compared to those infused with saline.

Concomitant administration of cyclosporin and ketoconazole in renal transplant recipients.

18 renal transplant recipients receiving cyclosporin, prednisone, and azathioprine were given ketoconazole, a potent inhibitor of the cytochrome P-450 enzyme system. Within a month ketoconazole-induced blockade of cyclosporin metabolism allowed a significant reduction (451 vs 106 mg/day; 77%) of the mean dose of cyclosporin without altering cyclosporin whole blood trough levels, although maximum blood levels were almost halved. This dose reduction was maintained in patients followed up for up to 13 months. Renal and hepatic function were unchanged after the addition of ketoconazole. This drug interaction has the potential to reduce dramatically expenditure on cyclosporin in transplant recipients.

Efficacy and safety of constant-rate intravenous cyclosporine infusion immediately after heart transplantation.

Oral cyclosporine therapy immediately after heart transplantation is erratic and difficult to predict. The purpose of this study was to evaluate the relative efficacy and safety of cyclosporine when administered by constant-rate infusion immediately after transplantation. Nineteen patients (17 men and two women) aged 50 years (range 25 to 61 years) who weighed 71 +/- 9 kg, participated in the study and received cyclosporine, 7 to 10 mg/hr (117 +/- 15 micrograms/kg/hr). The infusions were initially maintained for 26 +/- 5 hours (range 18 to 42 hours) without adjustments in dosage. Whole blood samples were obtained at hourly intervals for the first 8 to 12 hours and then daily throughout the 7-day study period and were analyzed by high-performance liquid chromatography. Constant-rate cyclosporine infusion resulted in therapeutic blood levels (350 to 450 ng/ml) at 6 hours. These levels remained relatively steady throughout the 7-day infusion, requiring only minimal dosage adjustments. Kidney function was not altered significantly after 7 days of intravenous cyclosporine therapy as evidenced by a mean serum creatinine level of 1.3 mg/dl before therapy and 1.4 mg/dl after therapy. There, however, was a transient rise in serum creatinine level in most patients on the second or third day after transplantation that resolved without a reduction in cyclosporine dosage. The mean endomyocardial biopsy score at 1 week after transplantation was 0.1, and only four of the patients required additional immunosuppressive therapy to treat rejection during the first 6 weeks after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical variability of cyclosporine pharmacokinetics in adult and pediatric patients after renal, cardiac, hepatic, and bone-marrow transplants.

The most important limitation associated with the clinical use of cyclosporine is the narrow therapeutic range between its efficacy and toxicity. Effective treatment is further complicated by significant variation in intrapatient and interpatient pharmacokinetics of the drug. We describe a practical approach to pharmacokinetic analysis that does not interfere with the cyclosporine dosage regimen or with clinical management of the patient. To optimize therapy, we individualized patient management by using noncompartmental pharmacokinetic analysis. Mean residence time (MRT) and volume of distribution at steady-state were calculated from data on concentration vs time after dose. We applied this approach to 24 kidney, 12 heart, 8 bone-marrow, 7 liver, and 5 pancreas transplants. Individualized requirements for cyclosporine dose and dosage interval can be predicted from these parameters. MRT is the most useful pharmacokinetic parameter, because it allows prediction of the optimal dosage interval.

Cyclosporine pharmacokinetics in pancreas transplant recipients.

Ten CsA pharmacokinetic studies were performed on five pancreas transplant recipients to determine proper doses and dosing intervals. These cadaver pancreas transplants were performed with exocrine ductal drainage into the urinary tract through a bladder anastomosis in four cases and into the bowel in one case. Four CsA pharmacokinetic studies were performed on diabetic renal transplant recipients and an additional six studies were performed while with pancreas transplant patients taking metoclopramide in an effort to enhance absorption of CsA. Mean CsA dose was 3.7 mg/kg/dose (range 2.1 to 7.5 mg/kg/dose). All patients but one were on twice daily dosing intervals yielding an average daily dose of 7.4 mg/kg/d. Noncompartmental pharmacokinetic analyses were used. The adequacy of a 1-, 2-, or 3-exponential model was determined by breakpoint analysis of the log concentration v time curve using the F statistic. The terminal rate constant was calculated by nonlinear regression analysis. The AUC and AUMC were calculated by the trapezoidal method with exponential extrapolation and these were used to calculate the MRT and Vdss. The unknown fractional absorption, F, was used to correct the oral data. The average CsA concentration maximum (Cmax) was 528 ng/mL with an average time to maximum concentration (Tmax) of 4.7 hours, a mean residence time of 7.75 hours, with a Vdss/%F of 9.61 L/kg in the pancreas transplant recipients. Additional studies of six patients receiving metoclopramide with CsA revealed an average Cmax of 723 ng/mL, an average Tmax of 2.3 hours, an average MRT of 6.08 hours, and an average Vdss/%F of 5.7% L/kg. These results indicate that coexistent gastroparesis in diabetic recipients of either pancreatic or renal transplants may result in reduced bioavailability of CsA.

Hepatitis B vaccination. Response of alcoholic with and without liver injury.

Alcoholics are at risk to develop hepatitis B infections, chronic active hepatitis, and even hepatoma. Hence, immunization with hepatitis B vaccine is recommended. However, immune abnormalities may coexist which alter their responsiveness to vaccination. This study compares the immune response to this vaccine in controls (group I), alcoholics without overt liver disease (group II), and alcoholics with clinical liver disease (group III). By the seventh month after the initial vaccination, 89% in group I, 70% in group II, and 18% in group III had a response greater than 36 RIA units. The magnitude of the response was significantly different in groups I, II, and III (19,456 vs 8,326 vs 153 RIA units, respectively; P less than 0.05, group I vs III). In those who did not respond, a significant (P less than 0.02) lower helper/inducer (T4) class of lymphocytes was observed as compared to patients who exhibited an adequate response. These observations suggest: (1) that the response to hepatitis B vaccine is a T-cell-dependent event and (2) that in this population, using the existing vaccine, postvaccination evaluations of antibody concentrations are needed before protection against hepatitis B infection can be assumed.

Effect of trimethoprim on serum creatinine in healthy and chronic renal failure volunteers.

The effect of trimethoprim (TMP) on serum creatinine concentration (SCr) was studied in 10 healthy (H) subjects and nine subjects with chronic renal failure (CRF). Each volunteer was given TMP 100 mg perorally every 12 h for 10 days followed by a 7-day washout period. SCr was measured colorimetrically immediately before the study (baseline), on day 10 of TMP, and 7 days after TMP had been discontinued. SCr increased an average of 14.8% from baseline during TMP administration in the H volunteers, but this increase was not statistically significant. During TMP administration to the CRF volunteers, a pronounced elevation (34.6%) of mean SCr from baseline was observed (p less than 0.05). SCr returned to baseline values in both groups following the 7-day washout period. These results are consistent with the hypothesis that TMP competitively inhibits the renal tubular secretion of creatinine.

Use of cyclosporine and ketoconazole without nephrotoxicity in two heart transplant recipients.

A cyclosporine-ketoconazole drug interaction was first described in 1981. It has been suggested that the two drugs should not be used concomitantly because of the danger of severe nephrotoxicity. Two reported cases indicate that cyclosporine and ketoconazole can be safely coadministered, provided that the dosage of cyclosporine is reduced appropriately. Two patients were initially given 8 mg/kg/day of cyclosporine at the time of heart transplantation, and the dosage was tapered to meet appropriate blood levels (250 to 350 ng/ml by whole blood high-performance liquid chromatography). During ketoconazole therapy (400 mg daily for 4 weeks), patient 1 received 80 to 100 mg/day of cyclosporine, which is equal to approximately 1 mg/kg/day, and patient 2 received between 40 and 80 mg/day of cyclosporine, which is equivalent to 0.4 to 0.8 mg/kg/day. Neither patient exhibited a creatinine value above 1.4 mg/dl while on combined therapy, and there were no problems with allograft rejection. Both patients had inappropriately high cyclosporine blood levels even with this marked reduction in dosage (patient 1, 520 to 1310 ng/ml and patient 2, 320 to 600 ng/ml). Thus it appears that cyclosporine and ketoconazole can be administered together safely, provided that there is an appropriate reduction in the dosage of cyclosporine; this results in the maintenance of adequate immunosuppression without development of nephrotoxicity.

The effect of oral metoclopramide on the absorption of cyclosporine.

This study was performed to determine the effect of coadministered oral metoclopramide on the absorption of oral cyclosporine in 14 kidney transplant patients with stable renal function. The study was conducted on two consecutive days. Ten patients were studied twice and four patients once, giving 24 studies. The total dosage of metoclopramide was 20 mg. The day on which metoclopramide was administered was chosen randomly. Whole blood cyclosporine levels were analyzed by high performance liquid chromatography. Coadministration of cyclosporine with metoclopramide resulted in a significant increase in mean maximum blood concentration (567 ng/mL nu 388 ng/mL) and mean area under the blood concentration nu time curve (4120 ng X h/mL nu 3370 ng X h/mL), and a significant decrease in mean time to reach maximum concentration: The mean increase in area under the blood concentration versus time curve was 29%. No significant changes were observed in the elimination of cyclosporine when it was coadministered with metoclopramide. These observations suggest that coadministered metoclopramide increased the total absorption of cyclosporine. Metoclopramide has been shown to hasten gastric emptying; since cyclosporine is absorbed predominantly in the small intestine, coadministration of metoclopramide resulted in increased bioavailability of cyclosporine.