Case Study VI Answers PHA 5127 Fall 2006

Transcription

1 Qustion. A ptint is givn 250 mg immit-rls thophyllin tblt (Tblt A). A wk ltr, th sm ptint is givn 250 mg sustin-rls thophyllin tblt (Tblt B). Th tblts follow on-comprtmntl mol n hv first-orr bsorption n limintion. Th biovilbility is 90% for both tblts. Th plsm rug concntrtion-tim profils for both tblts r s follows: Plsm Drug Conc. (mg/l) Tblt A Tblt B Dtrmin k, k, n V for both tblts. Formultion A: First plot th t on smi-log scl: Tblt A Plsm Conc. (mg/l) Looking t th plot, w cn uc th following:

2 ) Th lst four t points r firly linr n ssum to b th trminl phs b) Sinc th tblt is n immit-rls on, k >>k so th trminl phs rflcts k. F D k k t k t Cp V k k ( ) ( ) Dtrmin k : Tblt A: Trminl phs Plsm Drug Conc. (mg/l) y x R Bs on th xponntil rgrssion of th lst four t points: k t 0.77 t Cp" C 8.76 So k 0. hr - Dtrmin k : W cn us th fthring mtho (lso known s mtho of rsiuls) to fin k. Dtrmin Cp (s shown bov) by xtrpolting Cp (givn in th tbl on pg ). Fin th iffrnc btwn Cp n Cp, this will giv you (Cp -Cp). Th bsorption constnt k cn b trmin from th xponntil rgrssion of (Cp Cp). Tim (hrs) Cp Cp" Cp"-Cp

3 Tblt A: Fthring mtho for k (Cp"-Cp) {mg/l} y x R k t t From th rgrssion: ( Cp" Cp) C So, k 0.82 hr -. Dtrmin V : From th trminl phs rgrssion lin, V cn b trmin from th constnt C. D F k C V k k V ( ) mg 250mg hr.7 L V 8 260mg 8.7 mg L ( 0.82hr 0.hr ) 30L 260mg V 3

4 Formultion B: First plot th t on smi-log scl: Plsm Drug Conc. (mg/l) 0. Tblt B Looking t th plot, w cn uc th following: c) Th lst four t points r firly linr n ssum to b th trminl phs ) Sinc th tblt is sustin-rls on, k <<k (w hv flip-flop sitution) so th trminl phs rflcts k. F D k k t k t Pls not tht in th cs of flip-flop sitution, Cp. V k k Dtrmin k : Tblt B: Trminl phs ( ) ( ) Plsm Drug Conc. (mg/l) 0. y x R

5 Bs on th xponntil rgrssion of th lst four t points: k t t Cp" C So k hr - Dtrmin k : W cn us th fthring mtho to fin k. Dtrmin Cp (s shown bov) by xtrpolting Cp (givn in th tbl on pg ). Fin th iffrnc btwn Cp n Cp, this will giv you (Cp -Cp). Th bsorption constnt k cn b trmin from th xponntil rgrssion of (Cp Cp). Tim (hrs) Cp Cp" Cp"-Cp Tblt B: Fthring mtho for k (Cp"-Cp) {mg/l} y x R k t 0.5 t From th rgrssion: ( Cp" Cp) C So, k 0. hr -. Dtrmin V : From th trminl phs rgrssion lin, V cn b trmin from th constnt C. 5

6 D F k C V ( k k ) mg 250mg hr.74 L V 80.6mg V 29.4L 2.74 mg L 2 ( 0.hr 0.029hr ) 80.6mg V Qustion 2. For on-comprtmnt, first-orr bsorption n limintion, multipl orl ministrtion, stt whthr th follows prmtrs will incrs, crs, or no chng. (Hint: Us simultion fils to nswr this qustion) C ss, vg F D CL τ C F C ss,mx ss,min t ss, mx k ln k k k τ ( ) k τ ( ) k t / 2bs ln(2) k Prmtrs us: D 250 mg, τ 6 hrs, n 4, t /2bs 2hrs, V 30 L, CL 30 L/hr C ss,vg Fluctution, F t mx CL in hlv Doubl Dcrs Incrs sinc k is hlv τ is oubl Hlv Incrs Incrs F is hlv Hlv No chng No chng k is oubl No chng Incrs Dcrs 6

7 Qustion 3. A ptint is to b put on continuous iv infusion. Dvis osing rgimn (incluing loing os) for th ptint. (Assum th rug to follow on-comprtmnt mol n hs first-orr limintion). Following r th proprtis of th rug n th ptint: Ptint Wight Drug s hlf-lif (t /2 ) Volum of istribution (V ) Dsir vrg sty stt concntrtion (C ss ) 30 lbs 3 hrs.8 L/kg 7.5 μg/ml k k o o C ss CL C 7.5 μg.8 ml Loing Dos C k L kg V V Loing Dos 798mg ss ss C ss V t 2 ln(2) 00mL kg 30lbs ln(2) L 2.2lb mg 84 mg 3hrs 00μg hr g L 00mL kg mg 7.5 μ.8 30lbs ml kg L 2.2lb 00μg Qustion 4. Tru n Fls. Th bsorption rt constnt (k ) is lwys lrgr thn th limintion rt constnt (k ). FALSE 2. Th orl biovilibility of vry lipophilic, nutrl, high xtrction rug (showing linr phrmcokintics) ftr orl ministrtion of tblt is significntly ffct by th livr bloo flow, th plsm protin bining, n th issolution rt. TRUE 3. Cp mx n t mx r sufficint to ssss bioquivlncy. FALSE 7

8 Qustion 5. Fill in th blnks. If k << k for rug ministr orlly (typicl of sustin rls formultion), th rug is si to follow _flip-flop_ kintics. 2. Th mtho of rsiuls, lso known s _fthring_, is mns by which k n k my b sprt n clcult whn orl t is nlyz. 3. Th _biovilbility_ is th frction of n orl os tht ntrs systmic circultion ftr ministrtion. 4. Onc constnt rt infusion is strt, th tim rquir to rch sty stt lvls is pnnt on th _hlf-lif_ (multipli by 5) of th rug. 8