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Pharmacokinetics and pharmacodynamics of sustained release systems
I I. pp.
Journal qf Steroid Biochemistry. Vol. 457 to 459 Pergamon Press Ltd 1979. Printed in GreatBritain
PHARMACOKINETICS AND PHARMACODYNAMICS OF SUSTAINED RELEASE SYSTEMS K. FOTHERBY Department of Steroid Biochemistry, Royal Postgraduate Medical School, Ducane Road, London W12, England SUMMARY
Sustained release systems which have an anti-fertility effect for more than one month are considered. Injectable formulations, norethisterone oenanthate and particularly DepoProvera, have been widely used and appear to have little if any effect on metabolic processes. Levels of the gestagen in blood after injection of the formulation are now known and the rate at which the injected steroid is metabolized appears to determine the duration of inhibition of ovulation. The advantages and disadvantages of systems consisting of silastic capsules containing the contraceptive steroid, which are widely used in Latin America and India, are discussed. Future developments will probably be mainly concerned with systems composed of a biodegradable polymer-steroid complex which will provide controlled release of one or more steroids in a predetermined manner. This presentation will be concerned with agents which
have an antifertility effect for more than 1 month and which are injected intramuscularly or implanted subcutaneously The various types of preparations discussed are shown in Table 1. DepoProvera has been widely used [l] as an injectable contraceptive, an injection of 150 mg producing an antifertility effect for at least 3 months with a failure rate (Pear1 index) of less than 1.5. The second formulation, norethisterone oenanthate, has been less widely used; an injection of 200 mg produces an antifertility effect for more than 2 months but its efficacy is less than that of DepoProvera, the Pearl index when injected every 84 days being less than 3. In 1974 a ten centre comparative clinical trial of these two injectable preparations was undertaken by the World Health Organisation[2] and it was thought essential at the same time to compare the pharmacological effects of these two formulations on a number of metabolic functions, on haematological factors and on ovarian function and to correlate any changes produced with the blood levels of the administered gestagens. Some of the results of this latter trial, which was carried out in three centres, the WHO Research and Training Centres in New Delhi and Stockholm and the WHO Collaborating Centre for Clinical Research in London, are discussed in this presentation. Levels of medroxyprogesterone acetate (MPA) in blood rise rapidly after injection [3,41: levels of l-4 ng/ml are found during the first 10 days after injection and the concentration then remains at a rather constant level of O.Z+lS ng/ml for the next 2-3
The following trivial names were used: medroxyprogesterone acetate (MPA): 17a-hydroxy-C-methylpregn-4 ene-3,20,dione-17-acetate (DepoProvera is a microcrystaltine suspension of MPA): Norethisterone oenanthate: 17/?-hydroxy-l9-nor-l7a-pregn-4-en-2~yn-3-one-l7-oenanthate.
months. A similar range of values was obtained in the WHO trial. Kirton and CornetteES] were the first
to show that the long-term inhibition of ovulation produced by the injection of DepoProvera was due to the peristence in the circulation of small amounts of medroxyprogesterone acetate. In three subjects they found that measurable amounts of medroxyprogesterone acetate were present in the circulation for more than 200 days after injection of DepoProvera and that ovulation, as shown by an increase in the plasma progesterone level, did not occur during this time. Similar results were reported by Ortiz et aI.[4]. In the four women studied in Stockholm, MPA was detectable in plasma for at least 120 days and in one ‘subject for 260 days after injection. In this latter subject ovulation had not returned by this time. In two of the remaining three subjects luteal function as indicated by a plasma progesterone level greater than 5 @ml, occurred at about 170 and 200 days after injection and at times when the plasma levels of MPA had decreased below lOOpg/ml. As in the Swedish women, in subjects studied in New Delhi MPA was detectable in the circulation for at least 120 days but ovarian function appeared to return much earlier. After injection of norethisterone oenanthate plasma levels of norethisterone are usually within the range of 4-8 ng/ml within the first 2 weeks after injection. There is then an exponential fall in the levels and values of less than lOOpg/ml are usually reached within 46 to 110 days of injection [6,7,*8]. Similar values were obtained in the WHO trial. In women injected with norethisterone oenanthate, ovarian function is less suppressed than in those injected with DepoProvera and ovulation may return as early as the 7th week after injection [6,7]. In the clinical trial carried out by the World Health Organisation[2], the contraceptive effect of norethisterone oenanthate was high during the first 2 months after injection but thereafter it decreased. In the four Swedish women injected with norethisterone oenan-
457
458
K.
FOTHERLIY
thate, the return of ovulation was correlated with the rate of metabolism of norethisterone in that the two women who showed a rise in progesterone before the 84th day after injection metabolized norethisterone oenanthate more quickly than the two women who did not show any rise until 100 days after injection. In the Indian women norethisterone oenanthate was metabolized more slowly and levels of less than lOOpg/ml were not reached until more than 100 days after injection nor did ovulation return before this time. In a more recent study of the return of ovulation in women injected with norethisterone oenanthate [9] it was shown that two of ten women ovulated within 60 days of injection and a further five subjects showed evidence of follicular activity. By 90 days after injection six of the women had ovulated and a further three had shown signs of follicular activity. Whereas the pharmacological effects of DepoProvera have been widely investigated [l, 10) those of norethisterone oenanthate have been much less studied. It might be expected that the effect, if any, of the injectable preparation on metabolic parameters would be biphasic, the more marked effect tending to be produced with the first few weeks after injection when the plasma levels of the biologically active steroids are high compared with the subsequent period when plasma levels of the steroids are markedly reduced. However neither DepoProvera nor norethisterone oenanthate have been reported to produce any marked metabolic changes. In the WHO pharmacological trial, neither formulation produced any significant changes in glucose tolerance, plasma lipid levels, hepatic function as judged by the measurement of serum enzyme activities or in a number of haematogical analyses compared to pre-treatment levels when subjects were investigated at 1 month and 3 months after injection. The subcutaneous implantation of silastic capsules containing various steroids to produce an antifertility effect has been widely used in Latin America and in India (see review by BenagianoCll]). Although this method appears to be acceptable in many populations it does have some disadvantages in that (a) there is often a marked “burst” effect, the release of the steroid from the capsule within the first few days of placement being very much higher than subsequently, (b) for most steroids the diffusibility through the silastic membrane is low and as many as four to six cap-
sules may need to be implanted to obtain a sufficient plasma level of the steroid to exert an antifertility effect and (c) the in uiuo release rates may vary widely. In 12 women injected with six silastic capsules containing norgestrel the calculated in viuo release rates for the steroid ranged from 23 to 151 pg per day [12]. However a satisfactory antifertility effect using implantation of single capsules containing norethisterone acetate with a release rate of 18Opg steroid per day has been achieved [ 13). A controlled zero order release of the antifertility steroid may be obtained by incorporating it into a biodegradable polymer so that the steroid is released as the polymer degrades. Such a system consisting of norethisterone incorporated into a polylactidepolyglycollide polymer has recently been tested in baboons [14]. Although even with this system a small “burst” effect is obtained, thereafter there is a fairly steady release of the drug with concomitant breakdown of the polymer. It seems likely that such devices will be tested in the near future in humans. If this approach is successful it should be possible to develop a system which will produce an antifertility effect for more than a year ,with plasma levels of the active steroid very markedly lower than those observed with the currently used injectable formulations. Consequently the side-effects should be minimal. In addition these polymer-steroid combinations should be capable of modification for the controlled release of a steroid in varying amounts and also for the controlled release of more than one steroid simultaneously or consecutively. REFERENCES
Population Reports.: Injectables and Implants. Series K No. 1 KI-K16 (1975). World Health Organization Expanded Programme of Research, Development and Research Training in Human Reproduction. Multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids: norethisterone oenanthate and medroxyprogesterone acetate. 1. Use-effectiveness. Contraception 15 (1977) 513-533. Jeppsson S. and Johansson E. D. B.: Medroxyprogesterone acetate, estradiol, FSH and LH in peripheral blood after intramuscular administration of Depo-Provera to women. Contraception 14 (1976) 461-469. Ortiz A., Hiroi M., Stannyk F. Z., Goebelsmann U. and Mishell D. R.: Serum medroxyprogesterone acetate (MPA) concentrations and ovarian function following intramuscular injection of Depo-MPA. J. C/in. Endocr. Metab. 44 (1977) 32-38.
Table 1. Long acting formulations of contraceptive steroids Liquid injectable formulations DepoProvera (DMPA)--microcrystalline (1)
suspension of medroxyprogesterone acetate (150 mg/ml) Norethisterone oenanthate (NET-OEN)-oily solution (200 mg/ml) (2) Solid formulations Silastic capsule containing steroid-implanted subcutaneously, (1) non-biodegradable Biodegradable polymer incorporating steroid-can be prepared (2) for subcutaneous implantation or intramuscular injection
Long acting contraceptive steroids 5. Kirton K. T. and Cornette J. C.: Return of ovulatory cyclicity following an intramuscular injection of medroxy-progesterone acetate (Provera). Contraception 10 (1974) 39-45. 6. Howard G., Warren R. J. and Fotherby K.: Plasma levels of norethisterone in women receiving norethisterone oenanthate intramuscularly. Contraception 12 (1975) 45-52. I. Weiner E. and Johansson E. D. B.: Plasma levels of norethindrone after I.M. injection of 200 mg norethindrone enanthate. Contraception 11 (1975) 419-425. 8. Fotherby K., Howard G., Shrimanker K., Elder M. and Bye P. G. T.: Plasma levels of norethisterone after single and multiple injections of norethisterone oenanthate. Contraception 18 (1978) l-6. 9. Fotherby K., Howard G., Shrimanker K., Elder M. and Bye P. G. T.: Occurrence of ovulation in women receiving the injectable contraceptive norethisterone oenanthate. Contraception 18 (1978) 535-543. 10. Nash H. A.: DepoProvera: A Review. Contraception 12 (1975) 377-393.
459
11. Benagiano G.: Long-acting systemic contraceptives. In Reaularion of Human Ferrilitv (Edited bv E. DiczfaI&. Script&, Copenhagen (1977) pp. 32-3360. 12. Moore D. E., Subir R., Stanczyk F. Z. and Mishell D. R.: Bleeding and serum o-norgestrel, estradiol and progesterone patterns in women using o-norgestrel subdermal polysiloxane capsules for contraception. Contraception 17 (1978) 315-328. 13. Takkar D., Anandlaxmi P. N., Chandra V. L., Bhatnagar S., Yadava H. S., Laumas K. R., Hingorani V., Krishna U. R., Mandlekar A., Purandare V. N., Goyal V., Adatia A. and Virkar K. D.: Long-term contraception by a silastic implant-D containing norethindrone acetate in women. Conrraception 17 (1978) 341-354. 14. Gresser J. D.. Wise D. L.. Beck L. R. and Howes J. F.: Larger animal testing’ of an injectable sustained release fertility control system. Confraception 17 (1978) 253-266.
Journal qf Steroid Biochemistry. Vol. 457 to 459 Pergamon Press Ltd 1979. Printed in GreatBritain
PHARMACOKINETICS AND PHARMACODYNAMICS OF SUSTAINED RELEASE SYSTEMS K. FOTHERBY Department of Steroid Biochemistry, Royal Postgraduate Medical School, Ducane Road, London W12, England SUMMARY
Sustained release systems which have an anti-fertility effect for more than one month are considered. Injectable formulations, norethisterone oenanthate and particularly DepoProvera, have been widely used and appear to have little if any effect on metabolic processes. Levels of the gestagen in blood after injection of the formulation are now known and the rate at which the injected steroid is metabolized appears to determine the duration of inhibition of ovulation. The advantages and disadvantages of systems consisting of silastic capsules containing the contraceptive steroid, which are widely used in Latin America and India, are discussed. Future developments will probably be mainly concerned with systems composed of a biodegradable polymer-steroid complex which will provide controlled release of one or more steroids in a predetermined manner. This presentation will be concerned with agents which
have an antifertility effect for more than 1 month and which are injected intramuscularly or implanted subcutaneously The various types of preparations discussed are shown in Table 1. DepoProvera has been widely used [l] as an injectable contraceptive, an injection of 150 mg producing an antifertility effect for at least 3 months with a failure rate (Pear1 index) of less than 1.5. The second formulation, norethisterone oenanthate, has been less widely used; an injection of 200 mg produces an antifertility effect for more than 2 months but its efficacy is less than that of DepoProvera, the Pearl index when injected every 84 days being less than 3. In 1974 a ten centre comparative clinical trial of these two injectable preparations was undertaken by the World Health Organisation[2] and it was thought essential at the same time to compare the pharmacological effects of these two formulations on a number of metabolic functions, on haematological factors and on ovarian function and to correlate any changes produced with the blood levels of the administered gestagens. Some of the results of this latter trial, which was carried out in three centres, the WHO Research and Training Centres in New Delhi and Stockholm and the WHO Collaborating Centre for Clinical Research in London, are discussed in this presentation. Levels of medroxyprogesterone acetate (MPA) in blood rise rapidly after injection [3,41: levels of l-4 ng/ml are found during the first 10 days after injection and the concentration then remains at a rather constant level of O.Z+lS ng/ml for the next 2-3
The following trivial names were used: medroxyprogesterone acetate (MPA): 17a-hydroxy-C-methylpregn-4 ene-3,20,dione-17-acetate (DepoProvera is a microcrystaltine suspension of MPA): Norethisterone oenanthate: 17/?-hydroxy-l9-nor-l7a-pregn-4-en-2~yn-3-one-l7-oenanthate.
months. A similar range of values was obtained in the WHO trial. Kirton and CornetteES] were the first
to show that the long-term inhibition of ovulation produced by the injection of DepoProvera was due to the peristence in the circulation of small amounts of medroxyprogesterone acetate. In three subjects they found that measurable amounts of medroxyprogesterone acetate were present in the circulation for more than 200 days after injection of DepoProvera and that ovulation, as shown by an increase in the plasma progesterone level, did not occur during this time. Similar results were reported by Ortiz et aI.[4]. In the four women studied in Stockholm, MPA was detectable in plasma for at least 120 days and in one ‘subject for 260 days after injection. In this latter subject ovulation had not returned by this time. In two of the remaining three subjects luteal function as indicated by a plasma progesterone level greater than 5 @ml, occurred at about 170 and 200 days after injection and at times when the plasma levels of MPA had decreased below lOOpg/ml. As in the Swedish women, in subjects studied in New Delhi MPA was detectable in the circulation for at least 120 days but ovarian function appeared to return much earlier. After injection of norethisterone oenanthate plasma levels of norethisterone are usually within the range of 4-8 ng/ml within the first 2 weeks after injection. There is then an exponential fall in the levels and values of less than lOOpg/ml are usually reached within 46 to 110 days of injection [6,7,*8]. Similar values were obtained in the WHO trial. In women injected with norethisterone oenanthate, ovarian function is less suppressed than in those injected with DepoProvera and ovulation may return as early as the 7th week after injection [6,7]. In the clinical trial carried out by the World Health Organisation[2], the contraceptive effect of norethisterone oenanthate was high during the first 2 months after injection but thereafter it decreased. In the four Swedish women injected with norethisterone oenan-
457
458
K.
FOTHERLIY
thate, the return of ovulation was correlated with the rate of metabolism of norethisterone in that the two women who showed a rise in progesterone before the 84th day after injection metabolized norethisterone oenanthate more quickly than the two women who did not show any rise until 100 days after injection. In the Indian women norethisterone oenanthate was metabolized more slowly and levels of less than lOOpg/ml were not reached until more than 100 days after injection nor did ovulation return before this time. In a more recent study of the return of ovulation in women injected with norethisterone oenanthate [9] it was shown that two of ten women ovulated within 60 days of injection and a further five subjects showed evidence of follicular activity. By 90 days after injection six of the women had ovulated and a further three had shown signs of follicular activity. Whereas the pharmacological effects of DepoProvera have been widely investigated [l, 10) those of norethisterone oenanthate have been much less studied. It might be expected that the effect, if any, of the injectable preparation on metabolic parameters would be biphasic, the more marked effect tending to be produced with the first few weeks after injection when the plasma levels of the biologically active steroids are high compared with the subsequent period when plasma levels of the steroids are markedly reduced. However neither DepoProvera nor norethisterone oenanthate have been reported to produce any marked metabolic changes. In the WHO pharmacological trial, neither formulation produced any significant changes in glucose tolerance, plasma lipid levels, hepatic function as judged by the measurement of serum enzyme activities or in a number of haematogical analyses compared to pre-treatment levels when subjects were investigated at 1 month and 3 months after injection. The subcutaneous implantation of silastic capsules containing various steroids to produce an antifertility effect has been widely used in Latin America and in India (see review by BenagianoCll]). Although this method appears to be acceptable in many populations it does have some disadvantages in that (a) there is often a marked “burst” effect, the release of the steroid from the capsule within the first few days of placement being very much higher than subsequently, (b) for most steroids the diffusibility through the silastic membrane is low and as many as four to six cap-
sules may need to be implanted to obtain a sufficient plasma level of the steroid to exert an antifertility effect and (c) the in uiuo release rates may vary widely. In 12 women injected with six silastic capsules containing norgestrel the calculated in viuo release rates for the steroid ranged from 23 to 151 pg per day [12]. However a satisfactory antifertility effect using implantation of single capsules containing norethisterone acetate with a release rate of 18Opg steroid per day has been achieved [ 13). A controlled zero order release of the antifertility steroid may be obtained by incorporating it into a biodegradable polymer so that the steroid is released as the polymer degrades. Such a system consisting of norethisterone incorporated into a polylactidepolyglycollide polymer has recently been tested in baboons [14]. Although even with this system a small “burst” effect is obtained, thereafter there is a fairly steady release of the drug with concomitant breakdown of the polymer. It seems likely that such devices will be tested in the near future in humans. If this approach is successful it should be possible to develop a system which will produce an antifertility effect for more than a year ,with plasma levels of the active steroid very markedly lower than those observed with the currently used injectable formulations. Consequently the side-effects should be minimal. In addition these polymer-steroid combinations should be capable of modification for the controlled release of a steroid in varying amounts and also for the controlled release of more than one steroid simultaneously or consecutively. REFERENCES
Population Reports.: Injectables and Implants. Series K No. 1 KI-K16 (1975). World Health Organization Expanded Programme of Research, Development and Research Training in Human Reproduction. Multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids: norethisterone oenanthate and medroxyprogesterone acetate. 1. Use-effectiveness. Contraception 15 (1977) 513-533. Jeppsson S. and Johansson E. D. B.: Medroxyprogesterone acetate, estradiol, FSH and LH in peripheral blood after intramuscular administration of Depo-Provera to women. Contraception 14 (1976) 461-469. Ortiz A., Hiroi M., Stannyk F. Z., Goebelsmann U. and Mishell D. R.: Serum medroxyprogesterone acetate (MPA) concentrations and ovarian function following intramuscular injection of Depo-MPA. J. C/in. Endocr. Metab. 44 (1977) 32-38.
Table 1. Long acting formulations of contraceptive steroids Liquid injectable formulations DepoProvera (DMPA)--microcrystalline (1)
suspension of medroxyprogesterone acetate (150 mg/ml) Norethisterone oenanthate (NET-OEN)-oily solution (200 mg/ml) (2) Solid formulations Silastic capsule containing steroid-implanted subcutaneously, (1) non-biodegradable Biodegradable polymer incorporating steroid-can be prepared (2) for subcutaneous implantation or intramuscular injection
Long acting contraceptive steroids 5. Kirton K. T. and Cornette J. C.: Return of ovulatory cyclicity following an intramuscular injection of medroxy-progesterone acetate (Provera). Contraception 10 (1974) 39-45. 6. Howard G., Warren R. J. and Fotherby K.: Plasma levels of norethisterone in women receiving norethisterone oenanthate intramuscularly. Contraception 12 (1975) 45-52. I. Weiner E. and Johansson E. D. B.: Plasma levels of norethindrone after I.M. injection of 200 mg norethindrone enanthate. Contraception 11 (1975) 419-425. 8. Fotherby K., Howard G., Shrimanker K., Elder M. and Bye P. G. T.: Plasma levels of norethisterone after single and multiple injections of norethisterone oenanthate. Contraception 18 (1978) l-6. 9. Fotherby K., Howard G., Shrimanker K., Elder M. and Bye P. G. T.: Occurrence of ovulation in women receiving the injectable contraceptive norethisterone oenanthate. Contraception 18 (1978) 535-543. 10. Nash H. A.: DepoProvera: A Review. Contraception 12 (1975) 377-393.
459
11. Benagiano G.: Long-acting systemic contraceptives. In Reaularion of Human Ferrilitv (Edited bv E. DiczfaI&. Script&, Copenhagen (1977) pp. 32-3360. 12. Moore D. E., Subir R., Stanczyk F. Z. and Mishell D. R.: Bleeding and serum o-norgestrel, estradiol and progesterone patterns in women using o-norgestrel subdermal polysiloxane capsules for contraception. Contraception 17 (1978) 315-328. 13. Takkar D., Anandlaxmi P. N., Chandra V. L., Bhatnagar S., Yadava H. S., Laumas K. R., Hingorani V., Krishna U. R., Mandlekar A., Purandare V. N., Goyal V., Adatia A. and Virkar K. D.: Long-term contraception by a silastic implant-D containing norethindrone acetate in women. Conrraception 17 (1978) 341-354. 14. Gresser J. D.. Wise D. L.. Beck L. R. and Howes J. F.: Larger animal testing’ of an injectable sustained release fertility control system. Confraception 17 (1978) 253-266.