Leading Article
Chn PII~rm:Kolln~1. 20 (I): 1.14. 19'91 0)1 l-S963/'1 I{OO}I.{)()(JI ,S07.00/O C .... d,s Intfm~uon~1 I lmltW
.... 11 nahls tnC'''W ~~-
Novel Drug Delivery S ystems
An Ql'en 'iew of Their Impact on Clinical Pharmacokinetic S tudies
Partha S. Banerjee and Joseph R. Robinson School of Pharmacy. UnlvcrSH)' of WisconSin. MadIson. WisconsIn. USA
In the past. one of the major goals of pharmaceullcal research has been to s) nthesise or discover new chemical en\lltes wllh desirable therapeutic properties but without undesirable side cffects. In the past decade or so an alternative to this approach has evolved for some drugs. Pharmacokinetic and pharmacological studies have demonstrated that the rate and extent of drug absorption. rather than the dose. eventually determine therapeutiC properties in systemiC treatment (U rquhart et a1. 1984). This led to the development of drug delivery systems that achieve pharmacological selectivity not solely on the basis of chemical Structure but also on the baSIS of controlling the rate of de1I\'el1' (Goldman 1982). In the past 20 yurs pharmaceutical dosage forms have be
tB
,
('Theflpeutje system)
I
, I
A
In.\,ISiOr'! rile
Thoerlpel,lllC system delivery rite
BlDavllllbility -
AS)( 100%
AC
FlO. ... Absoll,lte blOlvlilability assessment of a therapunc HIr1~ 1986, With permiSSion).
5)'1lem (from
atively, the mean OS can be ploned as a function of the infusion rate. Determination of the fraction of the dose released during the dosing period allows calculation of the mean delivery rate of the system, with which a mean CSS is associated. The ratio of this plasma concentration to the one corresponding to an intravenous infusion at a rale equal to the calculated delivery rate of the system is the expression of the absolute bioavailability of the delivery system (fig. 4) As a measure of the degree of retardation, an additional parameter is often used, which is the duration of the plasma concentration above a certain specified concentration. The concentration is specified either arbitrarily (Skinhoj et al. 1984) or as 50% (Drewe et at 1988) or 75% (Jonkman et a1. 1989; Oosterhuis et aJ. 1988) ofC mu . One study, more appropriately, evaluated the duration within the therapeutic range (Lamont et al. 1987). Since the objective of controlled release delivery systems is to produce stable plasma concentrations, that are constant or within a narrow range, flu ctuation in plasma concentrations is another important parameter in their pharmacokinetic evaluation. Different approaches used in clinical pharmacokinetic studies to measure fluctuation are listed in table II. Dosage form index, defined as the ratio of emu
, •
to e nll n. was o neorlhc earliest m ethodS (Thccuwcs & Ba yne 1977 ). Figure 5 s hows ho.... thi S md c .~ can clearl y c \'aluatc thc s upen or performance of a t herape utic system (ZafTarom 1978). lis I mpon a nt sl rength (and weakness) IS thai 11measures bcha\ ioural c. . trcmcs. To allr\;alc lh ls proble m Bo.~ cn baum ( 1984) Introduced thc area dcv !30on method. In .... hleh thc AUCs of Ihc c . . pcn mcntal cunes and a standard cunc. used to describe thc release of the drug qua n llta l 1\e1~. arc com pared .
Rccenli). Marhcms 1'131. (1989) ulllised thc ralio of occu pa nq lime above a m im mum effecti ve conccn tratlon and length of Ihc curve 10 evaluate s uslalllcd release dosage form s. In a completely differe nt approach. 1 tsudy. instead of mcasunng fluetu:l llOnS in plasma concCnlration. de termined the relatl\e frequenc) ofpallents ",hose concentrat ion profiles he m the tartet concent ration range as a func tion of dose per kilogra m per dosage m ten a l (Schaefers et al. 1984), Vall ncr et al. (1983) ha\e proposed a biocq ul valence method fo r the evaluation of controlled release products tha t u tilises an.'a measurements, The ra tiO of area for the controlled release product 10 tha t of the con \'entlOnal product
T,ble II , D,lte.enl appI'oacl'les to evalu ate !h.ICII,I.II01l $porI$4I !rom controll& able reasons. This will be one area of major im-
porlance to clinical pharmacokine"ticists in the future. Rate
Chn PII~rm:Kolln~1. 20 (I): 1.14. 19'91 0)1 l-S963/'1 I{OO}I.{)()(JI ,S07.00/O C .... d,s Intfm~uon~1 I lmltW
.... 11 nahls tnC'''W ~~-
Novel Drug Delivery S ystems
An Ql'en 'iew of Their Impact on Clinical Pharmacokinetic S tudies
Partha S. Banerjee and Joseph R. Robinson School of Pharmacy. UnlvcrSH)' of WisconSin. MadIson. WisconsIn. USA
In the past. one of the major goals of pharmaceullcal research has been to s) nthesise or discover new chemical en\lltes wllh desirable therapeutic properties but without undesirable side cffects. In the past decade or so an alternative to this approach has evolved for some drugs. Pharmacokinetic and pharmacological studies have demonstrated that the rate and extent of drug absorption. rather than the dose. eventually determine therapeutiC properties in systemiC treatment (U rquhart et a1. 1984). This led to the development of drug delivery systems that achieve pharmacological selectivity not solely on the basis of chemical Structure but also on the baSIS of controlling the rate of de1I\'el1' (Goldman 1982). In the past 20 yurs pharmaceutical dosage forms have be
tB
,
('Theflpeutje system)
I
, I
A
In.\,ISiOr'! rile
Thoerlpel,lllC system delivery rite
BlDavllllbility -
AS)( 100%
AC
FlO. ... Absoll,lte blOlvlilability assessment of a therapunc HIr1~ 1986, With permiSSion).
5)'1lem (from
atively, the mean OS can be ploned as a function of the infusion rate. Determination of the fraction of the dose released during the dosing period allows calculation of the mean delivery rate of the system, with which a mean CSS is associated. The ratio of this plasma concentration to the one corresponding to an intravenous infusion at a rale equal to the calculated delivery rate of the system is the expression of the absolute bioavailability of the delivery system (fig. 4) As a measure of the degree of retardation, an additional parameter is often used, which is the duration of the plasma concentration above a certain specified concentration. The concentration is specified either arbitrarily (Skinhoj et al. 1984) or as 50% (Drewe et at 1988) or 75% (Jonkman et a1. 1989; Oosterhuis et aJ. 1988) ofC mu . One study, more appropriately, evaluated the duration within the therapeutic range (Lamont et al. 1987). Since the objective of controlled release delivery systems is to produce stable plasma concentrations, that are constant or within a narrow range, flu ctuation in plasma concentrations is another important parameter in their pharmacokinetic evaluation. Different approaches used in clinical pharmacokinetic studies to measure fluctuation are listed in table II. Dosage form index, defined as the ratio of emu
, •
to e nll n. was o neorlhc earliest m ethodS (Thccuwcs & Ba yne 1977 ). Figure 5 s hows ho.... thi S md c .~ can clearl y c \'aluatc thc s upen or performance of a t herape utic system (ZafTarom 1978). lis I mpon a nt sl rength (and weakness) IS thai 11measures bcha\ ioural c. . trcmcs. To allr\;alc lh ls proble m Bo.~ cn baum ( 1984) Introduced thc area dcv !30on method. In .... hleh thc AUCs of Ihc c . . pcn mcntal cunes and a standard cunc. used to describe thc release of the drug qua n llta l 1\e1~. arc com pared .
Rccenli). Marhcms 1'131. (1989) ulllised thc ralio of occu pa nq lime above a m im mum effecti ve conccn tratlon and length of Ihc curve 10 evaluate s uslalllcd release dosage form s. In a completely differe nt approach. 1 tsudy. instead of mcasunng fluetu:l llOnS in plasma concCnlration. de termined the relatl\e frequenc) ofpallents ",hose concentrat ion profiles he m the tartet concent ration range as a func tion of dose per kilogra m per dosage m ten a l (Schaefers et al. 1984), Vall ncr et al. (1983) ha\e proposed a biocq ul valence method fo r the evaluation of controlled release products tha t u tilises an.'a measurements, The ra tiO of area for the controlled release product 10 tha t of the con \'entlOnal product
T,ble II , D,lte.enl appI'oacl'les to evalu ate !h.ICII,I.II01l $porI$4I !rom controll& able reasons. This will be one area of major im-
porlance to clinical pharmacokine"ticists in the future. Rate
