DRUG DISPOSITION
elin. Pharmacokincl. 23 (4): 279-291. 1992 0312-5963/92/00 I0-0279/ $06.50/ 0 © Adis International Limited. All rights reserved. CPK1221
Liposomal and Lipid Formulations of Amphotericin B Clinical Pharmacokinetics Robert Janknegt. Siem de Marie, Irma A.J.M. Bakker-Woudenberg and Daan J.A. Crommefin Department of Clinical Pharmacy. Maasland Hospital. Sittard. Department of Clinical Microbiology. Academic Hospital Rotterdam Dijkzigt. Rotterdam. and Faculty of Pharmacy. Department of Pharmaceutics. University of Utrecht. Utrecht. The Netherlands
Contents 279 280 281
282 282 282 282 284 284 285 287 288 288 289
Summary
Summary I. In Vivo Disposition of Liposomes 2. Pharmacokinetics of Amphotericin B 2.1 Absorption 2.2 Distribution 2.3 Elimination 3. Pharmacokinetics of Liposomal Amphotericin B and Lipid Complexes of Amphotericin B 3.1 DMPC: DMPG Liposomes 3.2 Amphotericin B Lipid Complex 3.3 'AmBisome' 3.4 Amphotericin B Colloidal Dispersion (ABCD) 3.5 EPC: Chol: SA Formulation 4. Discussion 5. Conclusions
Amphotericin B remains a very important drug for the treatment of fungal infections despite its toxicity. Encapsulation of amphotericin B into liposomes appears to reduce the toxic effects and to improve the clinical efficacy. allowing higher dosages to be given. The exact mechanism behind the reduced toxicity is not yet known. Amphotericin B is widely distributed after intravenous administration as the deoxycholate solubilisate. The highest concentrations are found in the liver. spleen and kidney. Protein binding and binding to the tissues is very high. The fate of the drug in the body is not known in detail. Renal and biliary excretion are both low and no metabolites have been identified. The drug is still detectable in the liver. spleen and kidney for as long as I year after stopping therapy. The pharmacokinetics of the different liposomal amphotericin B or lipid complexes of amphotericin B, which were recently developed, are quite diverse. A number of these preparations, such as amphotericin B lipid complex (ABLC), 'AmBisome' and amphotericin B colloidal dispersion (ABCD) are in clinical development. Their pharmacokinetics depend to a large extent on the composition and particle size of the liposomes or lipid complexes. Relatively large structures such as ABLC are rapidly taken up by the mononuclear phagocyte system. whereas smaller liposomes remain in the circulation for prolonged periods. In all studies only the total amphotericin B (both free and liposome- or lipid-associated) concentrations were determined.
280
Clin. Pharmacokinet. 23 (4) 1992
There is a need for studies correlating clinical efficacy and tolerability of liposomal amphotericin B with the pharmacokinetic properties of these formulations.
Amphotericin B remains the drug of choice for a variety of invasive fungal infections. It is active against a broad range of pathogenic fungi, such as Candida spp., Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum and Sporotrix schenckii (Holleran et al. 1985). Amphotericin B is, however, not an ideal drug. It is highly lipophilic and practically insoluble in water. The drug is conventionally formulated for intravenous administration as a mixed micellar dispersion with deoxycholate as surfactant. Amphotericin B has to be given by slow intravenous infusion in dextrose 5%. Normal saline solution leads to aggregation of the colloid (Barriere 1990). Low electrolyte concentrations as are present in continuous ambulatory peritoneal dialysis solutions are compatible with amphotericin B (Janknegt et al. 1990). The infusion of amphotericin B-deoxycholate (AMBd) is often poorly tolerated and toxic effects are common (table I). Shortening the infusion-time results in an increase of the infusion-related side effects (Ellis et al. 1991); increasing the dosage will lead to a high rate of the chronic side effects. The fungicidal activity of amphotericin B is concentration dependent as is shown both in in vitro and in animal studies (Van Etten et al. 1991; Van't Wout et al. 1989). In a clinical study of in-
Table I. Adverse effects of amphotericin B-desoxycholate (after Barriere 1990)
Infusion-related
Dose-related
Nausea and vomiting Fever Chills Thrombophlebitis Headache Arthralgia Myalgia
Potassium wasting Magnesium wasting Anaemia Renal failure Bronchospasm Hypotension Cardiotoxicity
vasive candidiasis, Powderly et al. (1988) demonstrated that efficacy was related to the minimal inhibitory concentration (MIC) of the isolated Candida strains. There were no survivors among the 10 patients from whom Candida with an MIC of over 0.8 mg/L was isolated, whereas 9 out of 17 patients infected by Candida with an MIC of 0.4 to 0.8 mg/L survived. The high rate of clinical failure of amphotericin B in granulocytopenic and other immunocompromised patients could be the result of inadequate local tissue concentrations of active drug. Due this dose-related toxicity, the maximal tolerable dosage is 0.7 to 1.0 mg/kg/day, which may be suboptimal for clinical success. Encapsulating amphotericin B into liposomes or binding the drug to lipid complexes may overcome this efficacy limitation: by reducing the toxic reactions and preserving antifungal activity of amphotericin B, these formulations can be administered in higher dosages resulting in an increased therapeutic index (Coune 1988; Lopez-Berestein et al. 1985, 1989; Meunier et al. 1988, 1991; Sculier et al. 1988). However, the various formulations differ substantially in structure and in pharmacokinetic behaviour, which may have implications for their clinical usefulness.
1. In Vivo Disposition
0/ Liposomes
Liposomes are stable (electron)microscopic vesicles, ranging in diameter from less than 0.1 to over 20JLm in diameter. They are composed of 1 or more lipid membranes surrounding an internal aqueous compartment (Naessander et al. 1990; Ostro & Cullis 1989). A vast body of literature is available describing the different physicochemical and (bio )pharmaceutical aspects of these vesicular structures (Fielding 1991; Gregoriadis 1984; Knight 1981; Lichtenberg & Barenholz 1988; New 1990). Liposomes can be divided into 3 categories on the basis of their morphology:
281
Liposomal Amphotericin B
l. Large, multi-layered liposomes of variable size, called multi lamellar vesicles (ML V). 2. Large, unilamellar vesicles (LUV) with a more homogeneous particle size that are >O.I/-Lm in diameter. 3. Small, unilamellar vesicles (SUV) with a particle size of
elin. Pharmacokincl. 23 (4): 279-291. 1992 0312-5963/92/00 I0-0279/ $06.50/ 0 © Adis International Limited. All rights reserved. CPK1221
Liposomal and Lipid Formulations of Amphotericin B Clinical Pharmacokinetics Robert Janknegt. Siem de Marie, Irma A.J.M. Bakker-Woudenberg and Daan J.A. Crommefin Department of Clinical Pharmacy. Maasland Hospital. Sittard. Department of Clinical Microbiology. Academic Hospital Rotterdam Dijkzigt. Rotterdam. and Faculty of Pharmacy. Department of Pharmaceutics. University of Utrecht. Utrecht. The Netherlands
Contents 279 280 281
282 282 282 282 284 284 285 287 288 288 289
Summary
Summary I. In Vivo Disposition of Liposomes 2. Pharmacokinetics of Amphotericin B 2.1 Absorption 2.2 Distribution 2.3 Elimination 3. Pharmacokinetics of Liposomal Amphotericin B and Lipid Complexes of Amphotericin B 3.1 DMPC: DMPG Liposomes 3.2 Amphotericin B Lipid Complex 3.3 'AmBisome' 3.4 Amphotericin B Colloidal Dispersion (ABCD) 3.5 EPC: Chol: SA Formulation 4. Discussion 5. Conclusions
Amphotericin B remains a very important drug for the treatment of fungal infections despite its toxicity. Encapsulation of amphotericin B into liposomes appears to reduce the toxic effects and to improve the clinical efficacy. allowing higher dosages to be given. The exact mechanism behind the reduced toxicity is not yet known. Amphotericin B is widely distributed after intravenous administration as the deoxycholate solubilisate. The highest concentrations are found in the liver. spleen and kidney. Protein binding and binding to the tissues is very high. The fate of the drug in the body is not known in detail. Renal and biliary excretion are both low and no metabolites have been identified. The drug is still detectable in the liver. spleen and kidney for as long as I year after stopping therapy. The pharmacokinetics of the different liposomal amphotericin B or lipid complexes of amphotericin B, which were recently developed, are quite diverse. A number of these preparations, such as amphotericin B lipid complex (ABLC), 'AmBisome' and amphotericin B colloidal dispersion (ABCD) are in clinical development. Their pharmacokinetics depend to a large extent on the composition and particle size of the liposomes or lipid complexes. Relatively large structures such as ABLC are rapidly taken up by the mononuclear phagocyte system. whereas smaller liposomes remain in the circulation for prolonged periods. In all studies only the total amphotericin B (both free and liposome- or lipid-associated) concentrations were determined.
280
Clin. Pharmacokinet. 23 (4) 1992
There is a need for studies correlating clinical efficacy and tolerability of liposomal amphotericin B with the pharmacokinetic properties of these formulations.
Amphotericin B remains the drug of choice for a variety of invasive fungal infections. It is active against a broad range of pathogenic fungi, such as Candida spp., Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum and Sporotrix schenckii (Holleran et al. 1985). Amphotericin B is, however, not an ideal drug. It is highly lipophilic and practically insoluble in water. The drug is conventionally formulated for intravenous administration as a mixed micellar dispersion with deoxycholate as surfactant. Amphotericin B has to be given by slow intravenous infusion in dextrose 5%. Normal saline solution leads to aggregation of the colloid (Barriere 1990). Low electrolyte concentrations as are present in continuous ambulatory peritoneal dialysis solutions are compatible with amphotericin B (Janknegt et al. 1990). The infusion of amphotericin B-deoxycholate (AMBd) is often poorly tolerated and toxic effects are common (table I). Shortening the infusion-time results in an increase of the infusion-related side effects (Ellis et al. 1991); increasing the dosage will lead to a high rate of the chronic side effects. The fungicidal activity of amphotericin B is concentration dependent as is shown both in in vitro and in animal studies (Van Etten et al. 1991; Van't Wout et al. 1989). In a clinical study of in-
Table I. Adverse effects of amphotericin B-desoxycholate (after Barriere 1990)
Infusion-related
Dose-related
Nausea and vomiting Fever Chills Thrombophlebitis Headache Arthralgia Myalgia
Potassium wasting Magnesium wasting Anaemia Renal failure Bronchospasm Hypotension Cardiotoxicity
vasive candidiasis, Powderly et al. (1988) demonstrated that efficacy was related to the minimal inhibitory concentration (MIC) of the isolated Candida strains. There were no survivors among the 10 patients from whom Candida with an MIC of over 0.8 mg/L was isolated, whereas 9 out of 17 patients infected by Candida with an MIC of 0.4 to 0.8 mg/L survived. The high rate of clinical failure of amphotericin B in granulocytopenic and other immunocompromised patients could be the result of inadequate local tissue concentrations of active drug. Due this dose-related toxicity, the maximal tolerable dosage is 0.7 to 1.0 mg/kg/day, which may be suboptimal for clinical success. Encapsulating amphotericin B into liposomes or binding the drug to lipid complexes may overcome this efficacy limitation: by reducing the toxic reactions and preserving antifungal activity of amphotericin B, these formulations can be administered in higher dosages resulting in an increased therapeutic index (Coune 1988; Lopez-Berestein et al. 1985, 1989; Meunier et al. 1988, 1991; Sculier et al. 1988). However, the various formulations differ substantially in structure and in pharmacokinetic behaviour, which may have implications for their clinical usefulness.
1. In Vivo Disposition
0/ Liposomes
Liposomes are stable (electron)microscopic vesicles, ranging in diameter from less than 0.1 to over 20JLm in diameter. They are composed of 1 or more lipid membranes surrounding an internal aqueous compartment (Naessander et al. 1990; Ostro & Cullis 1989). A vast body of literature is available describing the different physicochemical and (bio )pharmaceutical aspects of these vesicular structures (Fielding 1991; Gregoriadis 1984; Knight 1981; Lichtenberg & Barenholz 1988; New 1990). Liposomes can be divided into 3 categories on the basis of their morphology:
281
Liposomal Amphotericin B
l. Large, multi-layered liposomes of variable size, called multi lamellar vesicles (ML V). 2. Large, unilamellar vesicles (LUV) with a more homogeneous particle size that are >O.I/-Lm in diameter. 3. Small, unilamellar vesicles (SUV) with a particle size of
