ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1992, p. 1280-1283 0066-4804/92/061280-04$02.00/0 Copyright ©) 1992, American Society for Microbiology
Vol. 36, No. 6
Impact of Bioavailability on Determination of the Maximal Tolerated Dose of 2',3'-Dideoxyinosine in Phase I Trials GEORGE L. DRUSANO,l.2* GEOFFREY J. YUEN,2 GENE MORSE,6 TIMOTHY P. COOLEY,3 MINDELL SEIDLIN,4 JOHN S. LAMBERT,5 HOWARD A. LIEBMAN,3 FRED T. VALENTINE,4 AND RAPHAEL DOLIN5
The Program of Clinical Pharmacology, Division of Infectious Diseases, Department ofMedicine, University of Maryland School of Medicine, 1 and the University of Maryland School ofPharmacy,2 Baltimore Maryland 21201; the Division of Hematology-Oncology and the Clinical AIDS Service, Department of Medicine, Boston City Hospital, Boston, Massachusetts 021183; Department of Medicine, New York University School of Medicine, New York, New York 10003 ; the Infectious Diseases Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 146275; and School of Pharmacy, State University of New York at Buffalo, Buffalo, New York 142606 Received 19 December 1991/Accepted 18 March 1992
The objective of this study was to determine the population pharmacokinetic parameters and the extent of absorption of 2',3'-dideoxyinosine, a nucleoside analog with activity against human immunodeficiency virus in vitro and in vivo, after oral and intravenous administration through the use of NON-linear Mixed Effects Modeling. The data were drawn from the pharmacokinetics section of an open-label, multicenter phase I study. One center administered ddI on a once-daily schedule. The other centers administered the drug once every 12 h. Drug was administered intravenously, and the plasma concentration-time profile was determined. Patients were then given the drug orally at twice the dose used in the intravenous portion of the study, and the pharmacokinetic profile was again determined. A 40-fold range of doses was examined. Forty-six human immunodefciency virus-infected patients were studied. Concentrations in plasma were determined by high-pressure liquid chromatography. Clearance of the drug from plasma was 47.7 liters/h/70 kg of body weight. The terminal half-life was 1.4 h. The volume of distribution in the central compartment was 18.8 liters/70 kg. Absorption was rapid, with an absorption half-life of 0.52 h. Bioavailability with once-daily administration was 27%. For twice-daily administration, bioavailability rose to 36%. This difference was significant (P 4 0.01). For doses of 12 h). As can be seen from the data in Fig. 1 and 2, the once-daily dosing schedule results in higher peak concentrations, as would be expected. Higher peak concentrations in plasma likely result in higher peak intracellular concentrations of the active triphosphate, which has a long intracellular half-life. There may then be a compensation for the somewhat lower bioavailability because of the presence of larger amounts of the active moiety, which has a long half-life, being formed. nuIn 2000
X
0
400 1
2i
4
5
S
7
6
i0
TM Own) FIG. 2. A simulated plasma concentration-time curve in a steady-state dosing interval for a prototypical 70-kg patient receiving 375 mg of ddl by mouth every 12 h.
POPULATION PHARMACOKINETICS OF ddl
VOL. 36, 1992
Another hypothesis that may account for the observation of no differences in return of CD4 counts is that the response to the drug could have been maximal at a relatively low dose, while the different initial CD4-positive T-lymphocyte counts seen among patients accounted for any differences in response. One issue which the difference in bioavailability does explain is the different maximal tolerated doses (MTDs) observed in the two trials. In the twice-daily dose trial, an acute MTD of 10.2 mg/kg/day was found when the drug was administered orally. This amounts to 4.3 mg of absorbed drug per kg/day. The next highest dose (15.2 mg/kg/day) amounted to 5.5 mg of absorbed drug per kg/day. For the once-daily dosing schedule, the acute MTD was 20.4 mg/kg/ day, which translates to 5.5 mg of absorbed drug per kg/day, with the next dose escalation providing 8.2 mg of absorbed drug per kg/day. Therefore, the phase I trials described here identified an acute MTD which differed by only a very small amount (an acute MTD between 4.3 and 5.5 mg of absorbed drug per kg/day but less than 8.2 mg/kg/day). Observation for longer periods showed that the MTD for once-daily drug administration fell to 3.2 mg of absorbed drug per kg/day (12 mg/kg/day when the drug was administered orally) (3), but did not alter the MTD for the twice-daily dosing schedule. The ultimate MTD for either schedule is therefore between 3.2 and 4.3 mg of absorbed drug per kg/day. The difference in bioavailability provides insight into the evaluation of the toxicity of the drug. The frequencies of administration evaluated here did not have an impact on the toxicity of the drug, once we accounted for differences in bioavailability. Analysis of phase I trials of antiretroviral agents should use measured exposures of the patient to drug instead of doses of the agent administered to that patient.
8.
9.
10. 11.
12.
13.
14.
15.
ACKNOWLEDGMENTS We thank S. R. Gitterman for cheerful help and advice. In addition, we acknowledge the thoughtful comments of Russell Martin, Lisa Dunkle, and Umesh Shukla, of the Bristol-Myers Squibb Company. This study was supported in part by a grant from the BristolMyers Squibb Company. REFERENCES 1. Ahluwlia, G., M. A. Johnson, A. Fridland, D. A. Cooney, S. Broder, and D. G. Johns. 1988. Cellular pharmacology of the anti-HIV agent 2',3'-dideoxyinosine. Proc. Am. Assoc. Cancer Res. 29:349. (Abstract.) 2. Brigden, D., and P. Whiteman. 1985. The clinical pharmacology of acyclovir and its prodrugs. Scand. J. Infect. Dis. 47(Suppl.):33-39. 3. Cooley, T. P., L. M. Kunches, C. A. Saunders, C. J. Perkins, S. L. Kelley, C. McLaren, R. P. McCaffrey, and H. A. Liebman. 1990. Treatment of AIDS and AIDS-related complex with 2',3'-dideoxyinosine given once daily. Rev. Infect. Dis. 12(Suppl. 5):S552-S560. 4. Cooley, T. P., L. M. Kunches, C. A. Saunders, J. K. Ritter, C. J. Perkins, C. McLaren, R. P. McCaffrey, and H. A. Liebman. 1990. Once daily administration of 2',3'-dideoxyinosine (ddl) in patients with the acquired immune deficiency syndrome or AIDS-related complex: results of a phase I trial. N. Engl. J. Med. 322:1340-1345. 5. Drusano, G. L. 1988. Role of pharmacokinetics in the outcome of infection. Antimicrob. Agents Chemother. 32:289-297. 6. Drusano, G. L., G. J. Yuen, J. S. Lambert, M. Seidlin, R. Dolin, and F. T. Valentine. 1992. Quantitative relationships between dideoxyinosine exposure and surrogate markers of response in a phase I trial. Ann. Intern. Med. 116:562-566. 7. Fischl, M. A., D. D. Richman, M. H. Grieco, M. S. Gottlieb, P. A. Volberding, 0. L. Laskin, J. M. Leedom, J. E. Groopman,
16.
17.
18.
19. 20. 21.
22.
1283
D. Mildvan, R. T. Schooley, G. G. Jackson, D. T. Durack, D. King, and the AZT Collaborative Working Group. 1987. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N. Engl. J. Med. 317:185-191. Frick, L. W., D. J. Nelson, M. H. St. Clair, P. A. Furman, and T. A. Krenitsky. 1988. Effects of 3'-azido-3'-deoxythymidine on the deoxynucleotide triphosphate pools of cultured human cells. Biochem. Biophys. Res. Commun. 154:124-129. Ho, H.-T., and M. J. M. Hitchcock. 1989. Cellular pharmacology of 2',3'-dideoxy-2',3'-didehydrothymidine, a nucleoside analog active against human immunodeficiency virus. Antimicrob. Agents Chemother. 33:844-849. Jarvis, S. M. 1989. Characterization of sodium-dependent nucleoside transport in rabbit intestinal brush-border membrane vesicles. Biochim. Biophys. Acta 979:132-138. Klecker, R. W., J. M. Collins, R. Yarchoan, R. Thomas, J. F. Jenkins, S. Broder, and C. E. Myers. 1987. Plasma and cerebrospinal fluid pharmacokinetics of 3'-azido-3'-deoxythymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin. Pharmacol. Ther. 41:407-412. Knupp, C. A., W. C. Shyu, R. Dolin, F. Valentine, C. McLaren, R. R. Martin, K. A. Pittman, and R. H. Barbhaiya. 1991. Pharmacokinetics of didanosine in patients with acquired immunodeficiency syndrome or acquired immunodeficiency syndrome-related complex. Clin. Pharmacol. Ther. 49:523-535. Knupp, C. A., F. A. Stancato, E. A. Papp, and R. H. Barbhaiya. 1990. Quantitation of didanosine in human plasma and urine by high-performance liquid chromatography. J. Chromatogr. 533: 282-290. Lambert, J. S., M. Seidlin, R. C. Reichman, C. S. Plank, M. Laverty, G. D. Morse, C. Knupp, C. McLaren, C. Pettinelli F. T. Valentine, and R. Dolin. 1990. 2',3'-Dideoxyinosine (ddl) in patients with the acquired immune deficiency syndrome or AIDS-related complex: a phase I trial. N. Engl. J. Med. 322:1333-1340. Larder, B. A., G. Darby, and D. D. Richman. 1989. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243:1731-1734. Moore, R. D., P. S. Lietman, and C. R. Smith. 1987. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J. Infect. Dis. 155:93-99. NONMEM Project Group. 1987. NONMEM user's guide, parts I-VI. Technical reports. Division of Clinical Pharmacology, University of California, San Francisco. Pizzo, P. A., J. Eddy, J. Falloon, F. Balis, R. F. Murphy, H. Moss, P. Wolters, P. Brouwers, P. Jarosinski, M. Rubin, S. Broder, R. Yarchoan, A. Brunetti, M. Maha, S. NusinoffLehrman, and D. G. Poplack. 1988. Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N. Engl. J. Med. 319:889-896. Schentag, J. J., I. L. Smith, D. J. Swanson, C. DeAngelis, J. E. Fracasso, A. Vari, and J. W. Vance. 1984. Role for dual individualization with cefmenoxime. Am. J. Med. 77(Suppl. 6a):43-50. Sheiner, L. B., B. Rosenberg, and V. V. Marathe. 1977. Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. Pharmacokinet. Biopharm. 5:445-479. Volberding, P. A., S. W. Lagakos, M. A. Koch, C. Pettinelli, M. W. Myers, D. K. Booth, H. H. Balfour, Jr., R. C. Reichman, J. A. Bartlett, M. S. Hirsch, R. L. Murphy, W. D. Hardy, R. Soeiro, M. A. Fischl, J. G. Bartlett, T. C. Merigan, N. E. Hyslop, D. D. Richman, F. T. Valentine, L. Corey, and the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. 1990. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD-4 positive cells per cubic millimeter. N. Engl. J. Med. 322:941-949. Yarchoan, R., H. Mitsuya, R. V. Thomas, J. M. Pluda, N. R. Hartman, C.-F. Perno, K. S. Marczyk, J.-P. Allain, D. G. Johns, and S. Broder. 1989. In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine. Science 245:412-415.
Vol. 36, No. 6
Impact of Bioavailability on Determination of the Maximal Tolerated Dose of 2',3'-Dideoxyinosine in Phase I Trials GEORGE L. DRUSANO,l.2* GEOFFREY J. YUEN,2 GENE MORSE,6 TIMOTHY P. COOLEY,3 MINDELL SEIDLIN,4 JOHN S. LAMBERT,5 HOWARD A. LIEBMAN,3 FRED T. VALENTINE,4 AND RAPHAEL DOLIN5
The Program of Clinical Pharmacology, Division of Infectious Diseases, Department ofMedicine, University of Maryland School of Medicine, 1 and the University of Maryland School ofPharmacy,2 Baltimore Maryland 21201; the Division of Hematology-Oncology and the Clinical AIDS Service, Department of Medicine, Boston City Hospital, Boston, Massachusetts 021183; Department of Medicine, New York University School of Medicine, New York, New York 10003 ; the Infectious Diseases Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 146275; and School of Pharmacy, State University of New York at Buffalo, Buffalo, New York 142606 Received 19 December 1991/Accepted 18 March 1992
The objective of this study was to determine the population pharmacokinetic parameters and the extent of absorption of 2',3'-dideoxyinosine, a nucleoside analog with activity against human immunodeficiency virus in vitro and in vivo, after oral and intravenous administration through the use of NON-linear Mixed Effects Modeling. The data were drawn from the pharmacokinetics section of an open-label, multicenter phase I study. One center administered ddI on a once-daily schedule. The other centers administered the drug once every 12 h. Drug was administered intravenously, and the plasma concentration-time profile was determined. Patients were then given the drug orally at twice the dose used in the intravenous portion of the study, and the pharmacokinetic profile was again determined. A 40-fold range of doses was examined. Forty-six human immunodefciency virus-infected patients were studied. Concentrations in plasma were determined by high-pressure liquid chromatography. Clearance of the drug from plasma was 47.7 liters/h/70 kg of body weight. The terminal half-life was 1.4 h. The volume of distribution in the central compartment was 18.8 liters/70 kg. Absorption was rapid, with an absorption half-life of 0.52 h. Bioavailability with once-daily administration was 27%. For twice-daily administration, bioavailability rose to 36%. This difference was significant (P 4 0.01). For doses of 12 h). As can be seen from the data in Fig. 1 and 2, the once-daily dosing schedule results in higher peak concentrations, as would be expected. Higher peak concentrations in plasma likely result in higher peak intracellular concentrations of the active triphosphate, which has a long intracellular half-life. There may then be a compensation for the somewhat lower bioavailability because of the presence of larger amounts of the active moiety, which has a long half-life, being formed. nuIn 2000
X
0
400 1
2i
4
5
S
7
6
i0
TM Own) FIG. 2. A simulated plasma concentration-time curve in a steady-state dosing interval for a prototypical 70-kg patient receiving 375 mg of ddl by mouth every 12 h.
POPULATION PHARMACOKINETICS OF ddl
VOL. 36, 1992
Another hypothesis that may account for the observation of no differences in return of CD4 counts is that the response to the drug could have been maximal at a relatively low dose, while the different initial CD4-positive T-lymphocyte counts seen among patients accounted for any differences in response. One issue which the difference in bioavailability does explain is the different maximal tolerated doses (MTDs) observed in the two trials. In the twice-daily dose trial, an acute MTD of 10.2 mg/kg/day was found when the drug was administered orally. This amounts to 4.3 mg of absorbed drug per kg/day. The next highest dose (15.2 mg/kg/day) amounted to 5.5 mg of absorbed drug per kg/day. For the once-daily dosing schedule, the acute MTD was 20.4 mg/kg/ day, which translates to 5.5 mg of absorbed drug per kg/day, with the next dose escalation providing 8.2 mg of absorbed drug per kg/day. Therefore, the phase I trials described here identified an acute MTD which differed by only a very small amount (an acute MTD between 4.3 and 5.5 mg of absorbed drug per kg/day but less than 8.2 mg/kg/day). Observation for longer periods showed that the MTD for once-daily drug administration fell to 3.2 mg of absorbed drug per kg/day (12 mg/kg/day when the drug was administered orally) (3), but did not alter the MTD for the twice-daily dosing schedule. The ultimate MTD for either schedule is therefore between 3.2 and 4.3 mg of absorbed drug per kg/day. The difference in bioavailability provides insight into the evaluation of the toxicity of the drug. The frequencies of administration evaluated here did not have an impact on the toxicity of the drug, once we accounted for differences in bioavailability. Analysis of phase I trials of antiretroviral agents should use measured exposures of the patient to drug instead of doses of the agent administered to that patient.
8.
9.
10. 11.
12.
13.
14.
15.
ACKNOWLEDGMENTS We thank S. R. Gitterman for cheerful help and advice. In addition, we acknowledge the thoughtful comments of Russell Martin, Lisa Dunkle, and Umesh Shukla, of the Bristol-Myers Squibb Company. This study was supported in part by a grant from the BristolMyers Squibb Company. REFERENCES 1. Ahluwlia, G., M. A. Johnson, A. Fridland, D. A. Cooney, S. Broder, and D. G. Johns. 1988. Cellular pharmacology of the anti-HIV agent 2',3'-dideoxyinosine. Proc. Am. Assoc. Cancer Res. 29:349. (Abstract.) 2. Brigden, D., and P. Whiteman. 1985. The clinical pharmacology of acyclovir and its prodrugs. Scand. J. Infect. Dis. 47(Suppl.):33-39. 3. Cooley, T. P., L. M. Kunches, C. A. Saunders, C. J. Perkins, S. L. Kelley, C. McLaren, R. P. McCaffrey, and H. A. Liebman. 1990. Treatment of AIDS and AIDS-related complex with 2',3'-dideoxyinosine given once daily. Rev. Infect. Dis. 12(Suppl. 5):S552-S560. 4. Cooley, T. P., L. M. Kunches, C. A. Saunders, J. K. Ritter, C. J. Perkins, C. McLaren, R. P. McCaffrey, and H. A. Liebman. 1990. Once daily administration of 2',3'-dideoxyinosine (ddl) in patients with the acquired immune deficiency syndrome or AIDS-related complex: results of a phase I trial. N. Engl. J. Med. 322:1340-1345. 5. Drusano, G. L. 1988. Role of pharmacokinetics in the outcome of infection. Antimicrob. Agents Chemother. 32:289-297. 6. Drusano, G. L., G. J. Yuen, J. S. Lambert, M. Seidlin, R. Dolin, and F. T. Valentine. 1992. Quantitative relationships between dideoxyinosine exposure and surrogate markers of response in a phase I trial. Ann. Intern. Med. 116:562-566. 7. Fischl, M. A., D. D. Richman, M. H. Grieco, M. S. Gottlieb, P. A. Volberding, 0. L. Laskin, J. M. Leedom, J. E. Groopman,
16.
17.
18.
19. 20. 21.
22.
1283
D. Mildvan, R. T. Schooley, G. G. Jackson, D. T. Durack, D. King, and the AZT Collaborative Working Group. 1987. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N. Engl. J. Med. 317:185-191. Frick, L. W., D. J. Nelson, M. H. St. Clair, P. A. Furman, and T. A. Krenitsky. 1988. Effects of 3'-azido-3'-deoxythymidine on the deoxynucleotide triphosphate pools of cultured human cells. Biochem. Biophys. Res. Commun. 154:124-129. Ho, H.-T., and M. J. M. Hitchcock. 1989. Cellular pharmacology of 2',3'-dideoxy-2',3'-didehydrothymidine, a nucleoside analog active against human immunodeficiency virus. Antimicrob. Agents Chemother. 33:844-849. Jarvis, S. M. 1989. Characterization of sodium-dependent nucleoside transport in rabbit intestinal brush-border membrane vesicles. Biochim. Biophys. Acta 979:132-138. Klecker, R. W., J. M. Collins, R. Yarchoan, R. Thomas, J. F. Jenkins, S. Broder, and C. E. Myers. 1987. Plasma and cerebrospinal fluid pharmacokinetics of 3'-azido-3'-deoxythymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin. Pharmacol. Ther. 41:407-412. Knupp, C. A., W. C. Shyu, R. Dolin, F. Valentine, C. McLaren, R. R. Martin, K. A. Pittman, and R. H. Barbhaiya. 1991. Pharmacokinetics of didanosine in patients with acquired immunodeficiency syndrome or acquired immunodeficiency syndrome-related complex. Clin. Pharmacol. Ther. 49:523-535. Knupp, C. A., F. A. Stancato, E. A. Papp, and R. H. Barbhaiya. 1990. Quantitation of didanosine in human plasma and urine by high-performance liquid chromatography. J. Chromatogr. 533: 282-290. Lambert, J. S., M. Seidlin, R. C. Reichman, C. S. Plank, M. Laverty, G. D. Morse, C. Knupp, C. McLaren, C. Pettinelli F. T. Valentine, and R. Dolin. 1990. 2',3'-Dideoxyinosine (ddl) in patients with the acquired immune deficiency syndrome or AIDS-related complex: a phase I trial. N. Engl. J. Med. 322:1333-1340. Larder, B. A., G. Darby, and D. D. Richman. 1989. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243:1731-1734. Moore, R. D., P. S. Lietman, and C. R. Smith. 1987. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J. Infect. Dis. 155:93-99. NONMEM Project Group. 1987. NONMEM user's guide, parts I-VI. Technical reports. Division of Clinical Pharmacology, University of California, San Francisco. Pizzo, P. A., J. Eddy, J. Falloon, F. Balis, R. F. Murphy, H. Moss, P. Wolters, P. Brouwers, P. Jarosinski, M. Rubin, S. Broder, R. Yarchoan, A. Brunetti, M. Maha, S. NusinoffLehrman, and D. G. Poplack. 1988. Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N. Engl. J. Med. 319:889-896. Schentag, J. J., I. L. Smith, D. J. Swanson, C. DeAngelis, J. E. Fracasso, A. Vari, and J. W. Vance. 1984. Role for dual individualization with cefmenoxime. Am. J. Med. 77(Suppl. 6a):43-50. Sheiner, L. B., B. Rosenberg, and V. V. Marathe. 1977. Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. Pharmacokinet. Biopharm. 5:445-479. Volberding, P. A., S. W. Lagakos, M. A. Koch, C. Pettinelli, M. W. Myers, D. K. Booth, H. H. Balfour, Jr., R. C. Reichman, J. A. Bartlett, M. S. Hirsch, R. L. Murphy, W. D. Hardy, R. Soeiro, M. A. Fischl, J. G. Bartlett, T. C. Merigan, N. E. Hyslop, D. D. Richman, F. T. Valentine, L. Corey, and the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. 1990. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD-4 positive cells per cubic millimeter. N. Engl. J. Med. 322:941-949. Yarchoan, R., H. Mitsuya, R. V. Thomas, J. M. Pluda, N. R. Hartman, C.-F. Perno, K. S. Marczyk, J.-P. Allain, D. G. Johns, and S. Broder. 1989. In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine. Science 245:412-415.
