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Pharmacokinetics of Amphotericin B and Flucytosine ANNEMARIE POLAK Dr Sc

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Pharmacokinetics of Amphotericin B and Flucytosine ANNEMARIE POLAK Dr Sc Postgrad Med J: first published as 10.1136/pgmj.55.647.667 on 1 September 1979. Downloaded from Postgraduate Medical Journal (September 1979) 55, 667-670 Pharmacokinetics of amphotericin B and flucytosine ANNEMARIE POLAK Dr sc. nat. Pharmaceutical Research Division, F. Hoffmann-La Roche & Co. Ltd, Basle, Switzerland Summary tolerated dose (1 0-1 5 mg/kg body weight or 50-100 The absorption of flucytosine from the digestive tract mg) was administered daily by the early investi- is very good but minimal with amphotericin B. For gators. But it gradually became apparent that a this reason, amphotericin B has to be injected intra- double dose on every other day was more effective venously. Fungistatic levels are achieved rapidly with and better tolerated. Bindschadler and Bennett flucytosine and slowly with amphotericin B, since the (1969) compared the amphotericin B levels in serum dose has to be increased slowly. Distribution of after a single and a double dose. At doses of from 5 flucytosine in other body fluids is high, whereas with to 50 mg, a correlation was found between blood amphotericin B it is poor. Flucytosine is excreted levels and daily doses. As the doses were increased, mainly via the kidney without metabolism, whereas inactivation or storage mechanisms seemed to amphotericin B is eliminated mainly by metabolism. disturb this correlation and limited the peak serum Protected by copyright. Therefore, amphotericin B dosage does not have to be concentrations of the drug. As might have been adapted to kidney function, which is the case for expected, infusions of up to 90 mg on alternate flucytosine. The half-life of flucytosine is short days gave higher peak levels than those obtained (hours), that of amphotericin B is long (days); flucy- with a daily dose of 45 mg. However, the minimal tosine is haemodialysable, whereas amphotericin B, concentrations were not significantly different so probably owing to the high protein binding, is not. that a similar antifungal activity could be expected. The drug given on every other day is much better Introduction tolerated, allowing the patient a day of rest between The pharmacokinetic properties of the intra- doses. More recently, the tendency has been for com- venous antifungal amphotericin B and of the oral paratively low doses to be given, e.g. 0-4 mg/kg body antifungal flucytosine differ fundamentally. In this weight daily or on alternate days. paper they are first discussed individually and then In order to avoid the severe side effects such as their effect when used clinically alone or in com- pyrexia and chills, treatment with amphotericin B bination is compared. is usually started in small doses which are gradually http://pmj.bmj.com/ increased during a period of 3-4 days. The disadvan- Amphotericin B tage of this is that the production of therapeutically Amphotericin B has been used as a chemothera- active serum levels is correspondingly delayed. Using peutic agent for more than 20 years. Yet investiga- a pharmacokinetic model, Atkinson and Bennett tions providing a rational pharmacokinetic basis for (1978) compared amphotericin B levels resulting intravenous or intrathecal treatment are scarce and from 2 different regimens: with the first, giving 1 mg several important phenomena poorly understood. on the first day and 5, 10 and 50 mg on the following During intravenous therapy, 90% of amphotericin B 3 days respectively, the serum levels necessary for on September 29, 2021 by guest. disappears from the blood although only consistently antifungal activity (0.2-0.5 mg/l) were reached only low levels are found in body fluids other than serum. on day 4 and were maintained for only 10 hr. With Moreover, the amphotericin B portion remaining the second regimen (25 mg on days 1 and 2, and 30 in the blood is strongly bound to serum proteins, mg on day 3) the critical serum level was reached on especially lipoproteins. day 2, and it was possible to maintain it. The second Dose recommendations for the safe and effective of these regimens was therefore recommended for use of amphotericin B are essentially based on the seriously ill patients. tolerance of patients receiving the drug. The highest Atkinson and Bennett (1978) studied carefully the pharmacokinetics of amphotericin B at the conclu- Correspondence: Dr Annemarie Polak, c/o F. Hoffmann- sion of treatment lasting 2-4 months. The distribu- La Roche & Co. Ltd, 124, Grenzacherstrasse, 4002, Basle, tion kinetic of amphotericin B was adequately Switzerland. described by a 3-compartment system: the drug is 0032-5473/79/0900-0667$02.00 © 1979 The Fellowship of Postgraduate Medicine Postgrad Med J: first published as 10.1136/pgmj.55.647.667 on 1 September 1979. Downloaded from 668 Annemarie Polak introduced into a central (intravascular) compart- intrathecal injection of the drug. The pharmaco- ment and distributed into 2 peripheral (extravascu- kinetics of intrathecally administered amphotericin B lar) compartments, of which the one is fast and the can be demonstrated using a 2-compartment model other slow to equilibrate. About 66% of the drug (Atkinson and Bindschadler, 1969). Amphotericin B is located in the latter compartment when the steady rapidly disappears from spinal fluid after initial state is reached. Initially, amphotericin B is rapidly administration. However, after a prolonged treat- eliminated, the half-life being about 24 hr. The ment, the half-life is increased because the second second terminal elimination phase, however, has a compartment serves as a reservoir, and amphotericin half-life of 15 days, indicating the high storage B is accumulated there. As in the serum model, the potency in the slow equilibrating compartment, identity of this compartment or pool is unknown. which has a volume of 220 litres with 30 compared TABLE 1. Concentrations of amphotericin B after intravenous litres of the other 2 compartments. The relative injection distribution volume is high (4 litres/kg), probably owing to the strong protein- and membrane-binding Concentration activity of amphotericin B. The amphotericin B Serum levels of 4 patients studied by Fields, Bates and (measured Abernathy (1970) accord well with results studied in Source Body fluid simultaneously) the model by Atkinson and Bennett (1978). The only (mg/l) (mg/l) speculation is about the exact location of the 3 com- Spinal fluid 0-05 1 -2-12 partments. Peritoneal 0-22-0-32 04-1-7 Elimination of the amphotericin B methyl ester Pleura 0-66 1-02 was in a similar to that of Joint 0-29 0-78 (given i.v.) explained way Bronchial secretion 0 -0-16* 1-36 amphotericin B by a 3-compartment model; how- humour 0-05-0-17 0-3-1-0** Aqueous Protected by copyright. ever, the overall elimination from serum was found 0-5 0-6-1-3 to be 4 times faster than for amphotericin B. With Uterus tissues ' on the day 1-26 1-26 5 mg/kg of amphotericin B methyl ester, peak serum Cord blood of 0.37 1-26 levels were 7-12 times higher than with 1 mg/kg of Amniotic fluidJ delivery 0-16 1-26 amphotericin B. In spite of this, nephrotoxicity was * Only immediately after injection. either absent or very weak (Jagdis et al., 1977). ** In rabbits with uveitis. Renal excretion of amphotericin B is negligible. Only 3% of the dose can be found in the urine. These careful studies of the pharmacokinetics of Pre-existing renal dysfunction had no effect on the amphotericin B will give a basis and guide for a more plasma levels of the drug. Even in anuric and effective and better tolerated treatment of systemic nephrectomized patients, the amphotericin B serum mycosis with amphotericin B in the future. levels and its elimination are exactly the same as in There are, however, still a number of unknown normal patients. Apparently, amphotericin B is pharmacological properties of the drug which eliminated mainly by metabolic conversion or by the should be studied further, e.g. the metabolism of bile (Craven, Ribble and Drutz, 1977). However, the amphotericin B and the identity of compartments http://pmj.bmj.com/ metabolites are not yet known. where amphotericin B is accumulated in the body. Concentrations in other body fluids after intra- venous injection of amphotericin B are rather low Flucytosine compared with the serum level (Table 1). On average, The absorption from the digestive tract is rapid the level of amphotericin B reaches 0.05 mg/l (2-4% and almost total. Peak levels of flucytosine were of the one in serum) in the spinal fluid. In the perito- measured 90-120min after oral administration if neal fluid, pleura orjoint, less than 50% of the serum kidney function was normal and 4-5 hr after if it levels are achieved. In bronchial secretion, a level was insufficient. The delay is because of the slow on September 29, 2021 by guest. of 0.16 mg/l was measured only immediately after elimination. the infusion and this declined rapidly. The concen- In volunteers and in patients, maximal serum con- trations in the urine are low. In the aqueous humour centrations in mg/l roughly correspond to the single of one patient, a high concentration (comparable to dose of the drug in mg/kg body weight (e.g. 30-40 that in serum) was measured, but considerably lower mg/l after a single dose of 30 mg/kg [Wade and concentrations were found in rabbits with experi- Sudlow, 1972; Schbnebeck et al., 1973; Dawborn, mental uveitis. Amphotericin B also crosses the Page and Schiavone, 1973]). For chemotherapy it is placenta (Bennett, 1975) (Table 1). necessary to maintain a steady state concentration Since the concentrations of amphotericin B in of between 25 and 100 mg/l.
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