Leadln. Article --------~----------~

Cion Pllarmacol ,R('I. 1\1 (6,: 425-433. 1990

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Therapeutic Drug Monitoring in Pregnancy Rationale and Current Status

Chrisrine Knoll and Felicity Reynolds Department of Pharmacolog). School of Pharmacy. London. and AnaesthetiC' Unit. U MDS. 51 Thomas's Campus. London. England

J. Monitoring Drugs in Pregnancy 1.1 Rationale

The rationale for mOnitoring drugs In preg­nancy is. of coursc. Ihe same as lhal for any patient group. It depends on a strong correlation between the unbound concentration of drug althe 'receplOr' (or other target) site and Ihe drug response. If the effects of such drug-receptor complexes can be as­sessed directly by clinical measurements, no fur­Iher improvement in palicnt management is achieved by therapeutic drug monitoring (TOM). This is the case for hypnotics. anticoagulants, di· uretics. hypogl ycaemics. hypolipidaemics, vaso­pressors. analgesics and some hormones. Other drugs. whose effects correlate highly with eoncen· tration at the site of action rather than with dose administered. those with narrow therapeutic dose ranges (e.g. phenytoin. lithium). and drugs whose toxic effects are indistinguishable from underlying diseases. are ideal candidates for TOM. For the majority of drugs, variations in patient response are a result of phannacokinetic rather than phar­macodynamic differences. and in pregnancy these differences are often amplified.

1.2 Free Venus Total Drug Conctntrntion Measurements

Ideally. the interstitial fluid bathing the target sites should be sampled to provide a dirf'Cl meas-

ure of pharmacologlcafly aC/II'£' drug. which is also the fraction available for metabolism and renal elimination. This. of course. is rarely practical but because the free . therapeutically active drug com­ponent equilibrates with that bound to plasma pro­teins it has become standard practice to use plasma or serum drug concentrations to provide an index of therapeutically acti ve drug. This is valid if the degree of protein binding remains constant but there are numerous instances when protein binding changes unpredictably. incl uding renal insuffi­ciency (Pacific et al . 1986). hepatic disease (George 1979). in patients receiving poly therapy with highly bound comedicants (Knott et al. 1982; Neuvonen et al. 1979: Patsa10s & Lascelles 1977) and with hypoalbuminaemia arising postoperatively (Elf­strom 1979). after severe burns (Bowdle et al. 1980a). in neonates and infan ts (Morsell i 1989). in pregnancy (Knott et al. 1986; Kra uer et al. 1984; Reynolds & Knott 1989). in old age (Patterson et a\. 1982) and with overdosing (personal observa­tions). In these situations, therefore. it is no longer valid to assume that plasma drug concentrations reflect the therapeutically acti ve concentrations. and such measurements become meaningless (Kilpa­trick el al. 1984; Knot! 1983). Instead, il is essen­tial to measure the plasma unbound drug concen­trations (fig. I) or, where possible, the saliva drug concentrations. which for some drugs accurately reflect them (Knott 1989),

426

2. Drug Disposition in Pregnllncy

The possibili ty of adverse effects of maternal drug administ ration on the developing fetus may result in reduced maternal compliance (fig. 2). This may appear to reduce drug clearance, as does re­duced oral drug absorption by vomiting or by ant­acid (Carter et al. 198 1) o r mineral ingcstion (Ca mpbell et al. 1988). which may be particularl y relevant wi th current interest in health products. Significant reductions in gastroinlestinal motility on ly occur during labour when absorption is also im pai red, and drugs may accumulate in the gul. After delivery their absorpt ion may result in greatly elevated plasma concentrations and undercsti­mated clearance values. However, dose require­ments may genuincly increase with changing ma-

eon __ I Ya ..I_ I .. _-

No

00.., __ Ya " 1nw. .... ceo.J --,

No

. Do they c:orr-. wIIh Ya - I ---~ •• 1klnI1

No

Do they conwInI ...., Ya I --- -cor ......... ,,,.?

No

-"'-!tug ITIOI ....... 'II

Fig. 1. A 'ded$lon Ire(" based o n the major faclors 10 ,on­sider when determining the yalue or Iher.ilpc"utie drug moni­tonn ...

Oln. Phurmucol. lnN. 19 (6) 1Y90

EC' I

1 AlbJmin 1

'FA 1-----J_ ::::---11 , ,

""""''''''I '. t ......... ~ Clearance I ..- Enzyme

Oral """.- I ioduedon - I' t

Dose raquil1Ml"le!llS I Fig. 2. rnnelpil\ rX10f"S which ;nn ... ~n..., mal~mal dow ~­

qUlrementS In prq.nancy: arT"()\tl'S dIow lhe: dllttuon or ellanl". Increased Yolume ordlsmbul1on (Vd) can Iol'>'er the: pta$ma COIK't'TItnlllon and onnuence lher.ilpevl O(" drill mOf11tonn ... and onCTI:ased elearance can alter dose ~ul~menls. ECF • e~­

t raccllular nUId Yolume: FFA - free fauy acids.

ternal physiology (fig. 2) in complian t women (Nau et at 1982).

Total body clearance (el). defined as the vol­ume of plasma cleared of drug per hour per kilo­gram bodyweight. may i ncrease in pregnancy. Dur­ing long tenn drug administration it is usually calculated as the ratio of the fraction (f) of dose absorbed in unit time (D) to the plasma concen­tration at steady-state «('55) (Voteh et al. 1988J. ac­cording to the fo llowing form ula:

fD CL: -­

C'. (Eo. I )

The use of the term 'steady-state' in pregnancy is not strictly appropriate, because pregnancy is the one condition in which the physiological state is reliably not ·steady'. However, useful information can be obtai ned from clearance data if account is taken of factors which may appear to alter ils v alue.

Drug concentrations may fall with maternal en­zyme induction. reflecting the balance between progesterone and estrogen concentrations (Loock

Drug MOflnonng In Pregnancy

ct al. 1988) and. to a lesser extent. the increasing contribution 10 drug metabolism by the fetal com· partmcnt (fig. 2) [Juchau 1982). Plasma dilution also lowers Ihe levels of plasma albumin and. less consISICIHI}. plasma <l'1-acid glycoprotein (Kraucr Cl31. 1984). which arc the major binding proteins for aCids 3nd basic drugs. respectively. Thus. mat­crnal prolein binding for many drugs is reduced during prcgnancy (Notarianni 1990). particularly 111 the last trimester and during labour (Bardy et al. 1990: Knoll 1985) when increased free fauy acid (FFA) concenlrations displace them from albumin (Albani et al. 1984: Krauer et al. 1986: Nau et a1. 1983). Plasma albumin measuremcnts cannot. therefore. predict Ihe extent of protein binding (Johnson et al. 1989: Pacifici el a1. 1986). and plasma unbound drug concentrations must be measured 10 provide information about drug ki­netics.

The volume of distribution (Vd) rises with in· creases in extraccllular fluid volume (ECF). fat content and the expanding fetal compartment (fig. 2). This has relatively greater effect on the Vd of polar drugs tha n on that of the already extensively distributed lipophilic drugs. Drug half-life (t'h) de­pends on the net changes in Vd and CL from the fo llowing equation:

Vd x 0.693 t ~ =

CL (Eq. 2)

The half-life may therefore increase. decrease or remain unchanged in pregnancy compared with the nonpregnant values. The laller are reported in table I. The clinical impact of altered drug disposition in pregnancy is d iscussed below. and the placental transfer of drugs is reviewed elsewhere (Reynolds & Knott 1989).

3, Drugs for which TDM is Meaningful

The early enthusiasm for routine TDM has evaporated somewhat in recent years. Disappoint­ments have arisen because some patients experi­ence unexpected responses to treatment compared with the 'normal' population, and arguments for monilOring have been weakened by the occurrence

427

of pharmacodynamic interactions. However, it is currently considcred important 10 measure lithium and phenytoin concentrations. useful 10 monitor theophyllinc, digoxin and peak and trough amino­glycoside conccntrations. and less essential bu t still useful 10 monitor the other anticonvulsants (table I). Further studies 3re required 10 validatc routint:' TOM for thc antidepressants. Despite good cor­relations between plasma total and unbou nd or sa­liva drug concentrations. and the logical reasons for measuring plasma unbound values, reference ranges arc traditionallY constructed for plasma.

The average populalion protein binding range is included in table I. but free fraction measure­ments vary wi th temperature. p H and the tech­nique used to separate bound from free drug. which are not always quoted. Ultrafiltration or centrifug­ation of plasma or serum may result in an under· estimation of the absolute frcc drug conccntration. unless it is measured al body temperature. wh ile equilibrium dialysis takes several hours to com­plete at 37"C, when rising plasma FFAs may dis­place highly bound drugs from albumin (Riva et al. 1982) and overestimate the free drug concen­trat ion. However. interlaboratory variations should be minimised if these lechniques arc performed at physiological temperature and pH. The advantage of frec drug reference ranges over those for total drug concentration in plasma is that they remain the samc irrespective of protein binding changes.

3.1 Assays

Drug assay techniques currently used fo r each of the groups arc listed in the last col umn in table L They reflect the continued trend towards a uto­mated microanalytical techniques with increased sensi tivity and accuracy, which have encouraged the making of much-needed improvements in in­terlaboratory sta ndardisation of methods.

3.2 Individual Drug Classes

3.2.1 Antibiolics Peak concentrations for the antibiotics (table I)

more appropriately reflect toxicity, while trough values (5 to 6 times lower) relate more to their

428 elm. PharmaC'Oktnt't. 19 (6) 1990

nble I. Drug, (Ind their active me,-bOIitlll tor wtIk;:h monitoring is considered UMtuI. TIM large! rlnges gi¥en ". tor plasma concentration, with 1Ja1lY. conotnlrltion in pilrenlheSH: I. data taken from the Iit«.turl

e .... '- " Target ""IY CI ... ,- I, Target A'NY

'"' i'I" .. ..,. ~, i'I" .. ..,. 'moIW I"'91L)

AntilirmythlNe. -- ... ," ..... ,~~ l --- .. ,., " .. ,. F~A (3.5-9) OLe (N __ 1yI- - , .. ". 81-93 111-20 (1-2) HPLC procainamlOe) Primidont .. " ... 5-1215-12) FPlA Digitend" 1)4. 192 90-97 13-25 "gILl RIA., EMIT Vllproic KkI 1· '5 "'95' ... ," [);goxln ",., 23-~ 1-2 "giL FPlA Antidepfe ... "ta DI.opyr.mlde <-10 111-65' ,.. FP'A

_M 15-25 80-95

OH" l Procalnlmlde ,l-5' " ... 10 F~A nortriptyline , .. " 90-95 0.05-0.15 Do."", 8·25 5-50 "OIL Ole.

AntIbIolle,C oorool<lpln >1 2 5-100 ... gfl HPLC Amlklcln 0.5-3 ... .. " AlA, Imlprlmlntl .. " 85-95 O.IH.25 RIA. FPIA

HLPC. _.- 12-24 75-90 O.O75-(l.18 F~A

"""" 111-24 0 O •• ..().8 MS. FES .... ~- 2-3 "'" <-" Fm _fl.' I~zld ,~,

" O.toO.' OI.C Katlllm'jd'l 0.5-3 0-30 , .. " F~A BtonchodilatoQ

Su_ 2-3 30 , .... Fm Theophyline .. ..... ,~,. HU'C, Tobrtmycln ~5 ~,. .. " AlA. EMIT, (4-10) EMIT.

HPCC Ole. FptA

V,ncomycln 4-10 10 ,..., FPIA Plychotropkl OiIlUlMlm _0 ..... 0,05.0.2 ! HPLC. AntIconyuluntl OMO .,,, 97 0.3-1 .2

Clrblmneplne '~30 75 .. " FUlzepam 24-48 S-2"g,lL OLC

(1 .5-2.8) GLC IO,l1-epoltide .. " 0.2·2,0-

HPLC (0.1-1.2)

FPIA ElhoIuxlmide .~ 0 .""

(0-100)

• OoM-dependenl.

b Oeneblty cletermlned.

c Adult 11'1 .nd peak plum. reference range. d Ringe ulended to 1.2 rnmoI/L In _CUI. "",n!tl . I It larglll rlno- nal not been established lor the epoxlde but IJIese .r. commonly .ncounlerld value • . At>brev/M;on.: I", - tennirlal half-life; r~ • bound fraction of drug in plasma: FPlA • fluorescence poIfIrlNtIon Immunoa,uy: AlA • r~S5'Y; EMIT • en~linked imtnunoessay: HPlC - I'Iigh pertom'Iance liquid dYomatogf~: GLe • gal liquid chrom.togr.phy: AAS •• tomic .bsorpIIon apectr~ FES • ft.",. emillion ~oecopJ; OMO • dctmethykIiuepam.

efficacy and depend on the infecting palhogen, se­veri ty of infection and time that the minimum in­hibitory concentration (MIC) is exceeded (Night­ingale \989). However, Grevel and colleagues (1989) have suggesld that greater therapeutic pre-

cision can be achieved frorp measurements of the area under the concentration-time curve (AUC) than from isolated trough concentration measure­ments in renal transplant patients. A knowledge of renal status is important as aminoglycosides and

Drug Monllorlng In Pr('gnanq

some cephalosporins produce nephrotoxicilY and ototoxicity at doses only slightly above the micro­biologically effective concentrations.

Many of these drugs arc poorly lipid soluble and prOiein bound, and are excreled largely unmela­bolised at the glomerular fillration rate (White et al. 198]), which increases in pregnancy (Dunlop 1979). Some newer cephalosporins arc highly bound (Lam el al. 1988), have lower CL and Vd but sim­ilar I.·" and show saturable binding which is dis­placed by FAAs. bilirubin and comedicants (Bialer el al. 1988; Decroix et at 1988). Their protein bi nd ing, therefore. is likely to fall in pregnancy.

In general. increased plasma clearances with either unchangcd or increased Vd and shorter ( .1,

arc reported for the aminoglycosides (Lazebnik et al. 1985), the penicillin derivatives (Kjer & Ollesen 1986) and the cephalosporins (Chow & Jcwesson 1985) in pregnanc),. and plasma concentrat ions fa ll below the MIC (Nau 1987).

3.1.1 Antiarrh)'lhmics These weak bases are highly ionised at physio­

logical pH and the)' arc absorbed erratically - a problem which may be worsened during preg­nancy, Disopyramide. like the cephalosporins, shows saturable binding at clinically effective con­centrations. For such drugs, unbound clearance values may be bener estimates as they change in­dependently of protein binding changes (Upton & Williams 1986). In a recent study using spiked plasma samples. disopyramide protein binding was found to be significantly lower in the second and third trimesters and significantly greater I month after delivery than in nonpregnant women (Echi­zen et al. 1990). Thus, regular monitoring of the free drug concentration is indicated during preg­nancy and Ihe puerperium.

Digoxin is poorly bound (table I). widely dis­tributed and almost exclusively disposed of by renal elimination. It has a very narrow therapeutic dose ratio. and the correlation between plasma concen­tration and effect is only significant at 6 to 8 hours after dosing. Hypot hyroidism, hypokalaemia, hy­pomagnesaemia and hypercalcaemia can all in­crease myocardial sensitivity so that toxicity may

429

occur at subtherapeutic concentrations (Keys & Stafford 1981), while some palients can tolerale concentrations in excess of 3 ~g/L Pharmacodyn­amic interactions with other antiarrhythmics, how­ever, raise questions as \0 the value of digoxin maintenance therapy and its TOM (Spector el al. 1988) olher than for confirmation of compliance or toxicity.

Maternal digoxin concentrations fall in preg­nancy (Aronson 1980) as renal clearance increases. and if dose increments arc made. they must be re­duced I}()sl parrum. Radioimmunoassays arc un­suitable in pregnancy because the)' show high cross­reactivi ty with endogenous digoxin-like sub­stances. found particularly in pregnancies with a high risk of complications (Koren et al. 1988),

313 Bronchodilalors Theophylline and the anticonvulsants arc Ihe

only drugs for which optimal concen tration ranges for saliva as well as plasma have been established (KnOll et al 1984) for routine TOM (table I). Agi­tation and tachycardia become increasingly evi­dent above 20 mg/L. coincident with saturation of the binding of Iheophylline to albumin. T hco­phylline is predominantly hydroxylatcd and de­methylated. although small amounts arc excreted unchanged; its metabolism may be inhibited by ci­metidine, propranolol and erythromycin. Theo­phylline protein binding is lo ..... cr in the third trimester of pregnancy than in nonpregnant women (Connelly el al. 1990). The plasma clearance and Vd both for theophylline and for caffeine are often reduced in pregnancy (Cartcr 1986; Scarcy et al. 198]) and plasma half-lives are generally in­creased, thus necessitating morc frequent monitor­mg.

3.2.4 Antidepressants The pharmacokinetics of the tricyclic and re­

lated an tidepressants have been reviewed by Sjoqvist and 8enilsson (1984) and Potter et a1. (1984). The dosage of these highly bound drugs predicts the CS~ poorly because they are cleared at a rate genetically determined by the hydroxylator status (Sjoqvisl & 8enilsson 1984), which may be

<30

funher modified by comedicants. smoking and diet (Ertshefsky et at 1988), Their demethylation and hydroxylation products are pharmacologically ac­tive and long-lasting. High plasma drug concentra­tions correlate well with card iotoxic and ot her ad­verse effects. and with their binding affinity at muscarinic. a-adrenergic. 5-hydroxytryptamine and dopamine receptors (Gram el at 1984).

The pharmacokinetics of these drugs have nOI been studied in pregnancy. but monitoring is ad­vocated for TDM (Percl 1988; Preskom el a!. 1988). and for confirm ing compliance and toxicity (Mea­dor-Woodruff el 31. 1988),

3.2.5 Lithium Although optimum lithium concentrations for

mania or recurrent unipolar depression range be.­tween 0.4 and 0.8 mmol/ l . for shen periods in acute mania. the upper limit may be extended to 1.2 mmol/L It is commonly believed that long term high dose therapy should be avoided due to the increased risk of serious neuro- or renal toxicity. However. Schou (1988) has emphasised the low likel ihood of renal failure resulting from lithium treatmenl.

Serum lithium concen trations are linearly re­lated to dose. and trough serum samples should be assayed (Schou 1988). Frequent monitoring is rec­ommended when starting therapy or I week after changi ng doses or preparations. and thereafter lith­ium concen trations should be reviewed quarterly (Brodie & Feely 1988).

In I st udy. serum lithium concen trations fell during pregnancy as a result of increased clearance, and returned to normal values a few days after de­livery (Schou et al. 1973). More recently. the im­ponance of monitoring lithium to assess its role in reducing recurrences of !X)stpartum psychosis was emphasised by Stewart (1988). Lithium is a recog_ nised teratogen (Krause et al. 1990) and is there­fore used with caution in pregnancy. It is essential to monitor lithium concentrations closely in preg­nancy and also in the puerperium, particularly if dose adjustments are needed .

Oln. Pharlllacol.;uw" 19 (6) 199()

3.2.6 Anticonvulsants This is the most thorough ly evaluated class of

drugs for the relation between clinical effects and plasma concentration. and optimum ranges arc well defined (table I). Phenytoin. which is highly pro­tein bou nd and undergoes saturable metabolism within its narrow therapeutic range. is the only drug whose clin ical effects have been shown to correlate better with plasma unbound drug or saliva values when protein binding is depressed, than wi th plasma concentrations of total drug (Kilpatrick et a!. 1984; Knott et al. 1982, 1986b; Reynolds et a!. 1976). In addition, monitoring using saliva is cheaper and quicker than the less direct measures of therapeutically acti ve drug.

Indications for monitoring the other anticon­vulsants are weaker. They are less highly bound, have broader dose ranges. and are subject to fewer clinically relevant binding interactions. However. plasma concentrations correlate beller than dose with reduction in seizure frequency, and plasma or saliva concentrations can be used to optimise therapy. Concerns about the teratogenic potential of vaJproic acid (Binkerd et al. 1988; Lammer et al. 1987). its s hon half.life, saturable binding (Bowdle et al. 1980b) and weak correlation 00-tween clinical effect and plasma concentration {Kilpatrick et al. 1987} have resulted in a recent trend towards monitoring solely to assess compli. ance rather than for management of therapy.

Concentrations of phenytoin (KnOll et al. 1986) and phenobarbital (Chen el al. 1982) fall in preg_ nancy. and the frec fractions increase. Plasma con­centrations of primidone, which i s unbound, may also fall (Nau et al. 1982) while those for ethosux­imide (Kuhnz et al. 1984) and carbamazepine (Kuhnz et al. 1983: Yerby et al. 1985) may in­crease, decrease or remain unchanged. although there is a tendency for the carbamazepine-I 0, II­epoxide concentrations to increase. Generally, the Vd and hepatic clearance of the anliconvulsants tend to increase during pregnancy, and more so for the highly bound drugs. Dose requirements in­crease, particularly for phenytoin, and dose in­creases must be reduced in the puerperium to avoid toxicity (KnOll et al. 1986).

Drug Mon1l0nng In PrC'gnanc)

4. Conclusions

Volumes of distnbu tlon Increase m pregnancy. p.1rtlcularl~ for polar drugs such as anllblOtlCS. dlg­oxm and lithium . .... hose renal cllmination also nses (fig. 3). LI \er blood now IS unchanged m splle of mereased cardiac output. and so the clearancc of highly cxtractcd drugs [c.g. lidocaine ( lIgnocalnc) and propranolol] IS unaffected. The clearance of drugs \\ Ith 101·\ extraction rates ...... hll;h depends on their protein bmdlng (e.g. phenytoin. theoph}lline and .... arfann) [Le\y & B3uer 1986J. m3} Tlse if blndmg IS sign ifican tl y depressed (Smallwood et a1. 1988). Unbound clear3nce values may better assess the magnitude of these ch3ngcs. however, since they do not depend on protem bi nding.

For most drugs the monitoring offrcc drug con­Cen tr3!10nS (or where possible saliva drug concen-

'"

tratlOns) is rccommcnded, on a mont hly basis in the firs t tnmester. then blmonthl }, and \\eekl} in the last month and m the fi rst month after dcliv­el). Since al: drugs cross the placenta and arc ex­crcted Into milk to a grea ter or lesser degrec (Re)­nolds & KnOH 19R9). assessment of nconatal s.1hva drug concem ratlons ma y be ~d\ antageous (KnOH CI a1. 198601).

Authors' Note

Few drugs havc been invcstlga ted adequalely In

pregna ncy, and wc wish 10 col1ale dala relating un­bound d rug concentra tions wit h clinical efTC(' ts. panicularl} m condilions of rcduced or changmg protem bindmg. We would be gra teful 10 hcar from an}one .... llling to collaborate y,lIh us.

High protein binding

Cl t Vd t '. t

High I lplcl lOIubility

Cl _

Vd t '. t

+-+

, + , +-+

, +-+

Ant>eonvuts.ants Cepllaiosponn,

Anhdepressan15 SalicylIC aCId

Benzodlazepones

Xanthlnes

pt.",,~ Amlnogl1C01ideS

(anbp)'rine) Lithium PeniCllhns

Low protein bindIng

Cl t Vd t t ... 1. +-+

l ow UpkI .oIubillty

Cl t Vd t , +-+

'. +

Fig. 3. PredIl::I~ chan&« m drug pharmacokmetlCS In prq,nanc), based on their ph)slochemlcal propcnles. with e.\ampks: f - 1I\ereased; •• decreased: . -- • no chance: CL • 10lal bod) plasma drug ckarance: Vd _ \oIumc of dlslrlbuuon: '. '" ttrmmal half·1Ift.

432

Re/eretrcu

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