Pharmacokinetics of Amikacin (BB-K8) in patients with normal or impaired renal function.

The pharmacokinetics of Amikacin (BB-K8) were determined after a single i.v. injection of 7.8 mg of the antibiotic/kg of body weight. It was administered to 10 patients with normal renal function and 19 patients with varying degrees of renal impairment. The elimination of Amikacin from plasma was seen to follow the course of an open two-compartment model system. From patients with normal renal function, values for the following pharmacokinetic parameters were obtained: alpha = 4.219 hr-1; beta = 0.292 hr-1; K12 = 2.218 hr-1; K21 = 0.859 hr-1; K13 = 1.432 hr-1; Vc = 3.125 1; Vp = 8.068 1 and Vdss = 11.193 1. As the relationship K12/K21 is greater than 1, it may be seen that there is a tendency for the antibiotic to accumulate in the peripheric compartment. Impaired renal function significantly diminishes the values recorded for alpha, beta, K12, K21, K13. Distribution volumes are significantly increased in patients with renal impairment. A linear relationship between the K13 of Amikacin and creatinine clearance is demonstrated. Adjustment of Amikacin dosage, according to the individual degree of renal impairment, may be obtained by spacing out the injections.     

Pharmacokinetics of cefamandole in patients undergoing hemodialysis.

The pharmacokinetics of Cefamandole was studied in 17 patients with terminal renal impairment, 10 of which were undergoing sessions of hemodialysis while 7 were in the period between dialysis sessions. An open two-compartment kinetic model was used to describe the bi-phasic decrease of the plasma concentrations of Cefamandole thus establishing the amounts of the antibiotic in the peripheral and central compartments together with the amount eliminated. All patients received an i.v. bolus injections of 15 mg/kg body weight. During the hemodialysis sessions, the pharmacokinetic parameters of Cefamandole were the following: alpha = 5.006 hr-1 beta = 0.182 hr-1 K12 = 2.598 hr-1 K21 = 2.147 hr-1 K13 = 0.441 hr-1 Vc = 5.700 l Vp = 6.190 l Vdss = 11.94 l It may be seen that there is a decrease in the overall elimination constant compared with that obtained during the periods between the dialysis sessions. A dosage regimen of multiple doses is established as a function of the pharmacokinetic parameters of the antibiotic for patients with terminal renal impairment undergoing periodic sessions of hemodialysis.     

Pharmacokinetics of cefoxitin in patients undergoing hemodialysis.

The parmacokinetics of Cefoxitin were studied after an i.v. administration of 15 mg/kg body weight in 17 patients with terminal renal impairment, 10 of which were undergoing 6 hr hemodialysis sessions. The average pharmokinetic parameters obtained from this kind of patient were the following: alpha = 2.88 hr-1 beta = 0.18 hr-1 K12 = 1.43 hr-1 K21 = 1.04 hr-1 K13 = 0.53 hr-1 Vc = 8.23 l Vp = 11.61 l Vdss = 19.84 l. The amounts of the antibiotic in the central and peripheric compartments are established together with the amount of the antibiotic eliminated as a function of time. The pharmacokinetic parameters are significantly different from those established in the period between dialysis sessions, and thus, the elimination constant reaches a value of 0.28 h-1. The degree of plasma protein binding of Cefoxitin is 41.46% during the hemodialysis sessions. A dosage regimen is programmed as a function of the pharmacokinetic parameters established for this kind of patient. It is recommended that an i.v. dose of 15 mg/kg body weight should be administered at the beginning and end of each dialysis session lasting 6 hours, when the periods between the sessions are 48 hours.     

Evaluation of ototoxicity of amikacin (BB-K8) by animal test (author's transl)]

Seventy Hartley strain guinea pigs (350 g body weight at start of the experiment) were used. BB-K8, gentamicin (GM) and kanamycin (KM) were given to the animals intramuscularly for 28 days at following various doses: (see article) These guinea pigs underwent a differential frequency pinna reflex test in wide frequency range from 20KHz to 0.5 KHz before the administration, during the injection and after the last one. For histopathological examination of the inner ears the guinea pigs were subjected to intravital fixation with Wittmaack's fixative under nembutal general anesthesia. Blocks including the bilateral temporal bones were removed from the skulls and then fixed in the same fixative for 1 similar to 2 weeks. After routine procedure for decalcification, dehydration and celloidin embedding, horizontal serial sections of the inner ears were made and stained with hematoxylin-eosin. The differential frequency pinna relfex test in the 70 guinea pigs indicated positive pinna reflex in 90% at 20KHz and in 100% at 15, 12, 10, 8, 6, 4, 3, 2, 1 and 0.5 KHz before start of the administration. Administration of the antibiotics for 28 days occasionally resulted in the pinna reflex loss which always involved the highest frequency, 20 KHz and then was followed in relatively regular succession by 15, 12, 10, 8, 6, 4, 3, 2, 1 and 0.5 KHz (Tables 1 similar to 8). On the other hand, histopathological examination of the inner ears disclosed that the loss of the outer hair cells in the spiral organ which are the most sensitive to the ototoxic antibiotics, occurred always at the basal end of the spiral organ and then spread from there to upper portion of the spiral organ (Tables 9 similar to 16). Based on the differential frequency pinna reflex test in the wide frequency range and extensive histopathological examination of the inner ears, ototoxicity of BB-K8 is considered to be more mild than GM. However, there was not so remarkable difference in ototoxicity between BB-K8 and KM in the present experiment. The result or examination of the guinea pigs received BB-K8 at 40 mg/kg and 100 mg/kg respectively for 28 days suggests that BB-K8 at expecting clinical dose, 500 mg per day (for 28 days) may be safe from ototoxicosis in the inner ears. In the vestibular organs of the animals received BB-K8 there was no decrease in number of the hair cells.     

Pharmacokinetics of ritanserin in patients undergoing hemodialysis

The pharmacokinetics of ritanserin were studied in five patients with chronic renal insufficiency and who were undergoing periodic hemodialysis. Immediately after breakfast, a single 10-mg ritanserin tablet was administered to each patient on a day that they did not undergo dialysis. Plasma ritanserin levels were measured by a specific high-performance liquid chromatographic assay sensitive to 2 ng/mL plasma. After the oral 10-mg dose, the average time to reach the peak plasma concentration, Tmax, was 4.4 +/- 2.2 hours in these uremic patients, with a range of 2 to 8 hours. The average peak plasma concentration was 73.6 +/- 26.9 ng/mL (range: 54.6-120.0 ng/mL). Compared with a previous study in healthy volunteers, the uremic patients had a slower absorption profile, with a 39% reduction in peak plasma concentration and mean delay of 2.5 hours in Tmax. The mean area under the plasma concentration-time curve for ritanserin (2031 +/- 636 ng.hr/mL) was 47% lower compared with that in healthy volunteers (3867 +/- 1413 ng.hr/mL). The observed delayed and lower ritanserin absorption in these uremic patients may be caused by the chronic use of antacids such as aluminum hydroxide and calcium carbonate in all patients and/or by concurrent pathologic changes in the gastrointestinal mucosa of these patients. The regular hemodialysis sessions every 2-3 days did not affect the elimination rate of ritanserin, as the terminal half-life in these patients (39 +/- 23 hr) is similar to that in healthy volunteers (41 +/- 14 hr).