LESSON 4 Intravenous Bolus Admi Multiple Drug Administration, and istration, Steady-State Average Concentrations onsecrives ‘Aker completing Lesson 4, you should be abe ts 1. Describe the principe of syperpastion and how it applies to multiple dog doting 2. Define steady state and desrbe how treats to 8 chugs hte 3. Calcite the estimated peak plasma concentration sor multiple dug dosing (sendy sat) tm nial practic, most phamacokineue dosing Desired with onc-compartnen, cermin if Son modes at steady state. Using these models, we Gan hain a elimination sate corse (X} and then Galas volume of derivation (and doving inter {al based on thin Kalu Soy oor dicusion 4s en Limited single Intovenous (1) bolas dose of drug Most clinial stations however Tequre a therapeutic effect fr time periods aod Jogbyond the effet of one dove In these situations, ‘ukiple doves of drug ave piven, The goal 6 Anna thespeutie ets My hecping the amount rug in he ody, as wl asthe eoneentatlon of hog inthe pan, wits acy Constant range {ie rape sn) ta ten, we const haons for prediring dng concentrations afer IBikipie IV doses. although intermediate equations SE tied, only the nal equation i ingoriant to mendes ee 4. Caleloto the estimsted ough plasms concent tion aftr mule dug doing fat tan te). 15, Understand the equation for tcumulton factor at stoedy sate, INTRAVENOUS BOLUS DOSE MODEL Although not used often cially, the simplest example of makiple dosing che administration of apd 1 dones (boluses) of drug a constant me Ines n which the drug i represented by enecomparment adel ‘with sodertimination, [i cunicar Correvare “This lesson desebes 9 Sion, IV bots pharmaccinese model, tls used ony strate corain math concepts thet wil be futher ‘explored withthe move commonly ured IV inter {ent infusion (IV piggyback models described Lesson 5. Consequenty, ony read tis 1V our sec tion for genera! ‘understanding, knowing “hattis seldom applied inkcaly146 ConcapsinCinicalPhoracokinties iL so) hi’ ‘I . ‘e Tie FIGURE 44. Fars dg concentaor era et doe ‘The Best dose produces a plasma drug concenteation venus tne curve ke he one fn Figure Gy NOW feted tas Cy meaning maximum concenation © feoup le ih te other peak conceneations dat cour ‘seh mupe dosing Ie second bos doe is adinisteed before the frst, owe te completely eliminated, the maximum concent tion ater the abcond dose (Cy) ill be higher than that after the it dose (Chua ie 42). The wood part the curve wl be wey star to he fist cove bt trl be higher Gave a greter convention) because nme drug rains rom the frst dove wher the second ‘hae a anise, “Tne cme between administration of doses ede dos ing interval. “The dosing interval, symbolized by the (Geek fever tu (0), determined by 2 dogs hae Rapidly eliminated drugs (ue, those having 9 shor hale Iie) genealy have to be given more frequent shore ‘9, han drugs with longer ale It dig flows Rrstorder elimination (Le, the Bac tio of rg liminaed per tini ofe const), Den plas dg concentration ter multiple dosing canbe prodicted from concentasons aor a singe dose. This Iethod ues the principle of superposition, = simple res ecrique the ealy doses of erg do no abt 4 the pharmacskinetics (2 absorption ae earace) of ‘sequent doae, then plasma Gr conconation te fur tie cares after each dose wl ook the ses they ‘willbe sapermpoeble. The only erence Is that tbe {cual concenuations may be higher at later doses, cause dug has acum ‘Recall that the giatereept is called Gy and tha slope ofthe lie s -K_Furthermore, the drag cance {raom at any te (6) after the ist IV oles dose srenty. InG.=InGy-Kt (See Equation 3.2) Gee Fig second 1V bole dose i amined ater the dosing toen interval (but before de at sei completely el rate, Rete C= Cye at anytime () afer the hoe, lows tha ad Co * Goa val hot ‘hese Gyn he concentration fast Hef the nad St owe igen andthe dosing iteval, othe ne Now | Cm 0G 1 “anc the sam of Gyn 24 Ca (GUE 439, tht gona a Cont Goa "Co | wed a wd Guns * Coase ] Coa Goat * Coa By rearranging, we ge ‘concentaton ig cae) FIGURE 42. Pama ig concentration retulting from zcond dose. Smee” Cont #0) | ot rhe treet ful rr FIGURE 43. Enna elton,, son 4 ravenous Bolus Adminstration, Multiple Drog Adnan, and SteadyState Average Concetations 47 FIGURE 44, A thin V bolus dose can be administered ater the same dosing imterval (Tho plasma dog concenrason ‘ern tie proie evel further neease nthe man ‘im cancers immeshately ater the thin dose, 08 shown Figure 4 Jano fcr te is doves Gana = Gnas hic seston Cay alsa + FE Gna Gora + Grant hich sabsuting fr Gan ea Cail + XE + Gy. Tis simplifies flows Gras * Epanlll + HE +1) = Comilo o2F 4 1] = Gomll + o4F 0267 ‘swe can ee a pote emerger—afor any number ‘fining intervals the maximum concentration wil be: Cn * Ct +O 82 hI ‘phere msde numbor of doses even This euaton can De simpiied by mathematical proeutes toa mone use. ftfonn op PYRE Cou ithe concentration just after n aurser of tis are Bren. So, if we kaow Con, the elizaton Hi, and the dosing interval we can pred the man PM plasma concentration ater any mime (0) of on, Weal know that Crane Cguceneaton just bene 3 owe sven) equals Cane ™ These “Thisaer change allows calla Cy ie know the dase and volume of distribution oil stustion in lial practice Inea ofthe precoding equations the ern (te) (1 =e") appear ei alled the ecumltion fact because st eltes dg concetation ster a ingle dene to drug concent afer doses with mulipe do. Ing. This fetor ina marber greater tha which nd. fates how much higher te encentaton will baer n does compared withthe fet dose For example, i 100 doses ofa conan dug are sven toa pti, where R~ (8.0 nrand ¢~ Shou, the acemulation factor cal ‘ated a fltows fe"). or moaw'nny 7 ‘This means that the peak (or rough) concentration ter 100 doses wal he 08 times the peak (or ough) ‘onoentration after the rst dase. ‘The accumulation fctor fortwo or tee doses can also be’ ealeulated wo predie concentatone, bere Achievement of steady-state. Remember 303 tion fetor = 1ST) Bh scuntin ator = 2) ‘ofr de second IV bolus dase accumsan factor _( (teodbeed = gy to. ‘0670) ar For the thin 1V bolas dose: sccuradaton factor _(I=e 4%) (hee doses) ~ (gam 0309 tt -2n148 Concepts in Cincl Pharmacies: FIGURE 45. soma dg concentration verstine “therfore, ater two of dhree doses, de observed pel ‘rag voncentaion willbe 1-87 oF 2.12 times the peak oncenuation after the fie dace, respectively. The Concept of accutilation factor Is dcussed in more fleas the section Accumulation Factor laee sn this Tesron These equations wil be uso tr to rei roy a contains fr given dotage repens Por certain Akay {Ci aminopyeoides, ii rmporant to predic peak (Ck itnd tough (Cau) concentaions in varius cin (ater INTRAVENOUS BOLUS EQUATIONS AT STEADY STATE As sucarsive doses of drug are administered, the drug igi to aocumulte im dhe body. With st-order elim fm the amount of drug elimiaated per unit of ime Tmportonal to the anioune of drux in the body ‘okumuttion continues until the rate of elimination opreathes the rat of anise abn ate of drag going in = rate of dug going out ‘asthe rate of drug eiination increases and then appnates at of dru administration, she maxims {ak and suisimom (Wough) concentrations tmrease (Peatan eglbrium is reached. ater that pois, there STH be no addon acoomalation; the maximum and Trinimam conoentsatione wil remain constant with ich rueeguont doar of de (Pe). d | a H 3 u Hi 7 j = i feces j — { ‘when this equilriam gocuss, the maxim (and sninima) drag concentrations ae the same fr each Mona dose ven (asamang the same dove ad do Ing imeval are eae), When the maximum (ad mn imum) drag concentrations for sutzsave doses are the ‘ime, the amount of deug eliminated over the dst rv ate ut) equals Ue dose administered (tei) find the condition of steady states reached. ‘Stuady state wil always be Feached afer repeated rug administration atthe some dosing interval i hl dig ftles foseondeecimination. However, the Wns loque to reach steady sate varies from dre. dv Alepending om tie elimination tate constant With Her elimination rate constant (a shorter hale) reniy sate reached sooner than wih alower one Tonger alee) Pgute 47), "May mate te pot at which the amount fd administered over s dosing fotreal equals the atmo ie diue being eliminated over that same peti’ and ‘hull dependent on the elimination rate constant ‘hereon, wher the ena tate highs # {moun o drug beliminated over a given tine inter itunen esa sorter time fr the amount of dg eb {hated andthe amount oF ug administered obec ftealent (and, heretoe, achieve steady sate). 1 fittest drug ie known, the tme to seach sta ae canbe determined: I repeated doses of deur Soman FIGURE 47. Flay ste aeeched sooner with dug hang ashore rie‘ase a. Porcontage of Steady State Concentration Reached Darston f Deg ‘Steady State Concentration [nistrtion haletives) Reached ©) 7 30 2 % 3 ars 4 9375 5 96875 ‘ 9.735 7 925 (gon ata Bred interval, then in one hale he plasma fonctions wil reach 50% of thowe at steady tate ly the end ofthe socond halt the concentzatons lle 73% of steady stat, and 0.0n as shown in Tle [LL The plasma concentrations wil incest by proses tively smaller increments or all praoal pepo ‘etady sew be reached afer appatimaey fro oe Fades the concentrations at seady sate may be ‘bread eC, Foradrug such as gentamicin, with a -to thous hall Iie paints with roeral renal fonction, stoadystate foncentraon is achiewed within 10-20 hous forages hich at dgorn and phenobarbital, however a work of Tongsr my be needed to reach tay see With mulliple drug doses (Figure steady state lsreached when the drug from the Best dove i alot ntiey eliminated from the body. At this pat, the Amouat of drug remaining ftom the fat dose does fot conrbute significantly to the total amount of deus inthe body After e single dose, approximately four or Bve haitiver are required forthe body t0 fthminate the amount of drup equivalent fo the one ose: However at steady state, the amownt of dig guiaien co one dose is eliminated over one dosing Interval. Tis appacenty faster elimination isa result of accumulation of drag in the body. Although the tame percentage of drug i eliminated per hour, the Wester amount of drag in the body at seady wate fauses 3 eater amount to be eliminated over the fame time period The average times to each steady-state for some formmonly sed drags are shown in Tile 42. These may vary considerably between individuals and Tay he alired by disease. Hor some drug (3, asp ‘ns tating, and gentamicin), the, therpoutc wil begin before aeadysate plata concer fare reached. For others (eg. zidovudine. or im, 4 much Longer time povod. than that Jus Adninistraton, Malle Drug Admineratin, and Steady-State Avera Concentrations 49 Sencomescn FIGURE 48, ‘ready Sat, ine egret ne one of ‘rag one doing tara, seeded to reach steady sate is necessary fo fall the pens beneit 1 £ ee ee an a == ao oe i ‘caedated tom average dro has.aa 150 Concaptsin Cnc! Pharmacokinetics FIGURE 49. Dots inrees with no change indigo achiwe Nghe concent, ‘The time to reach steady state i determined by the drags elimination rat constant (K), but what eter ‘mines the actual plasma drag concentsation achiewed? [Ar Heady state, he levels achieved depend on the ‘ug’ clearance, volume of dstibution, dove, nd ‘osing interval (2, When equivalent dases are given, {drug witha low ellminaton rate constant and smal volume of dstinaton should achewe higher steady ‘Sate plasma concentatiogs than sn otherwise sin lar agene witha high eligination rate constant and lange volume of distribution. Inthe remainder of tls lesson, we examine some aspects of multiple dra dosing. ‘Steady-state concentrations ae commonly ierened ino wane ‘Method 1 Increase the drug dose but maintain the sme dosing interval (9, a8 shown in Pigue 43, Which real i wider uctations between the ‘asim (peak) and mnimem teh) concent tone afer each dae + Method 2—Roep the same dose ba give more fe {quently os shown in Figure £10, which reduces he Aiterences between the peak and wough concent ‘Note dha the te to aleve steady sate is the same both figures, In deciding ona speci dosing eglmen fora pater the pal i to achieve a cerain plasma concentration rag at steady state Tally, peak and tough concente tone wl both be eithin the therapeutic range (gs “a, ACCUMULATION FACTOR Equations can describe the plasma concentrator 4nd. pharmacokinetics of 2 ug at cody. sat Remember, steady sate will be teached only af Iouror five hativen, Roca ha with a IV bok nection of drag ti 4 one-compastent model and Bester elimina FIGURE 410, Dating nee decrase wih no change in dose achive Fehr coneataton, FIGURE 411 Maintoraneof pla dug concertos within the thereLason A nevenous Bolus Administration, Muliple Dr Adminstration, nd SteadyState Average Concentrations St he drag concentration at any Ue (ater any number ff dows (n), not necessarily at steady sat, can be (served by. Hop 7 1 prot the plasma concentration ofa drug at any time fatter n number of doses, we therefore need 10 ow fu alu + drag dose (9), tolume of isrbuton (7), 4 linnition rate constant (x), nd 1 dosing mterel ‘As mip drug doses ae administered, increases aod approaches tiie (abbreviated ax nb). The p= ding esuaton cag then be implied Asm become Tie umber." approaches «-~, which aprattes ‘iy S01 approaches 1 As 1c approaches Ththe valve ofthis amerate becomes tan the es ne namersterdeneminator combination i termed the ‘ccumalation factor a seal tate A ole 2 rem CConsequerty, the equation dove can now be rewiaen Aodesrbed the Cyay Concerta at steady sate: Ife wish o predic the steadysate peak concentration immedisely ser an IV boles doe where® = Donde a1 the eqlation above for Cy hocomes me = Iasi fer the dae eats 220 0. and = 1) ‘Wenn (he numberof doses piven) ise are (24 doses) the equation above simples: roy Camo F We can estimate the minimum or ugh convent on st steady sate. The trough concentration occ tat before dhe adminitadon ofthe net dow (att = inthis stustion, the general equation fr the exuaton Cy becomes: Note the simiarty between the esuatons for pent 24 Gea any Te RPE OF emer ge yey tiene ‘val ema! equation Oi) canbe ed a Gelato te concentra at any time air the pea. The ony aeence fats replace by te tine elapsed Sache ps ee. Teen Gu Coes ae where sth die afer dhe peak. hiss relaonshp very ust in clinical pharma kinetics Its realy the samo a an equation presented tarlie (Ser Equation 3.2) Gace ‘The preceding equation, sated in words, means “2 oncentaton at any time (Cs equal Yo ome previous ‘eoncentaon (Gq) multiplied by the facdon (or pe ‘ent of that previous concentration (Le, «emai ing after i has been allowed tbe eliminated fom the ‘bay fora numberof hours repressed by TE two dug concentrations and the time between, ‘hem are known, Kean be alesse, [fone concent ton afer a dave (ex, posk concentration) and K are now, then other concentrations at anytime afer 9 dose (blue the next dose) ca be ett, AVERAGE STEADY-STATE CONCENTRATION WITH INTRAVENOUS BOLUS DOSING ‘We now have examined both the maximm and mini ‘mum concessions that oo at sendy eat, Another ‘soft! parameter in multiple IV dosing stations ithe ‘verageconcrntalon of drug in the plasma at steady sate (C) (igure #12). Bocause Is independent of ans ‘hamacokinetic model, tis help the practicing ce rican (model assumpisons da not have tbe made). © sotan arithmetic or goometric mea. ‘Several mathematical methods maybe wed cle lute the average drug concenzation, bat onl anes pe sented here. plasma drug concentration versus dime fare afler stad tte has been achieved with 1V dos