CLINICAL PHARMACOKINETICS

Clin, Drug Invest. 9 (4): 197-205, 1995 11 73·2563/95/ OOO4-o197/ S04.5O/ 0

© Adis International Lim it ed . All rights reserved .

Clearance Prediction and Drug Dosage in Pregnancy A Clinical Study on Metildigoxin, and Application to other Drugs with Predominant Renal Elimination M. Gonser, P Stoll and P Kahle Department of Obstetrics and Gynaecology, University Hospital of Tiibingen, Tiibingen, Germany

Summary

The clearance of drugs with predominantly renal elimination is increased in pregnancy. The approach given in this paper for clearance prediction is based on the concept of parallel renal and nonrenal elimination, and on the assumption that clearance is increased as a result of a pregnancy-induced increase in the renal component, while the nonrenal component is assumed to remain essentially constant. The expected elimination capacity is then defined as the ratio of pregnant to normal nonpregnant clearances (QPr = cVCL), and can be calculated by the following equation: QPr=QNR+ (l-QNR) 01.5, where QNRis the normal, nonrenal elimination fraction. The expected elimination capacity provides a first estimate for the dosage adjustment, performed either by increasing the maintenance dose, D: d = D QPr, where d is the adjusted maintenance dose, or by reducing the dosage interval, T: t = T/QPr, where t is the adjusted dosage interval. We tested this approach for clearance prediction with pregnant and nonpregnant clearance data of metildigoxin, ampicillin and cefuroxime. Data on metildigoxin were obtained from 8 patients treated for maternal or fetal indications according to published recommendations. The observed clearance was significantly higher than the normal nonpregnant value (183 vs 140 ml/min), and closely matched the predicted value (189 mllmin). Clearance predictions for ampicillin and cefuroxime were performed using published data, and again close agreement was found between predicted and published clearance values. 0

When drug administration cannot be directly titrated against clinical effect, a knowledge of drug kinetics is crucial to management. In pregnancy, however, predictions regarding drug kinetics and dose adjustments are very difficult, because of the large pharmacokinetic variabilityJI ,2] Effective renal plasma flow (ERPF), glomerular filtration rate (GFR), and consequently endogenous creatinine clearance [CLCR ] increase early in pregnancy to approximately 50% above nonpregnant values. 13· 7]

These changes may be accompanied by a parallel increment in the renal elimination capacity of drugs. Therefore, the maternal concentration of drugs with predominantly renal elimination can fall during pregnancy,II,8,9] and dosage adjustment may be necessary during pregnancy to maintain therapeutic efficacy, as well as postpartum to avoid toxic effectsJIO,II] About 20 years ago, Dettli and coworkers[12-14] published simple rules for predicting elimination

198

and adjusting dosage when renal elimination capacity is reduced. The purpose of this paper is to extrapolate Dettli's approach from reduced to increased renal elimination capacity, and subsequently to predict the pregnancy clearance of drugs with predominantly renal elimination. Given that this approach can be applied to pregnancy, dosage adjustment of such drugs is a 2-step procedure: first, prediction of the relative increase in drug clearance, and second, either increase of the maintenance dose, D, or reduction of the dosage interval, T, of a mUltiple dosage regimen. We applied the first step, i.e. prediction of drug clearance, to treatment with metildigoxin (Bmethyldigoxin) in pregnancy. Treatment was planned following published recommendations.l 15.21 ] Drug clearance was calculated from measured steady-state blood levels and was compared with the predicted clearance as well as the normal nonpregnant clearance values. Finally, we tested the procedure for clearance prediction with published data on pregnant and nonpregnant clearance values of ampicillin[22] and cefuroximeP3]

Theory According to Dettli,l13,14] the individual drug clearance capacity is defined as the ratio Q of the individual to normal drug clearances: Q = c1fCL. Dosage adjustment is then accomplished either by: • adjusting the maintenance dose, D: d = D • Q (Rule 1), where d is the adjusted maintenance dose, or by • adjusting the dosage interval, T: t = T/Q (Rule 2), where t is the adjusted dosage interval. These dosage rules were originally established for reduced drug clearance (i.e. Q 1, Appendix I). Clearance prediction, i.e. prediction of the individual drug clearance capacity Q, is based on the concept of parallel nonrenal and renal elimination: cI = CL NR + c1 R, and on the assumption that drug clearance, c1, is changed as a result of a change in © Adis International Limited. All rights reserved.

Gonser et a/.

the renal elimination component c1R (normal parameters are written in capital letters, and individually changed parameters in lower case letters). The individual drug clearance capacity, Q =cl/CL, can then be derived from the unchanged nonrenal drug elimination fraction QNR = CLNR/CL, the changed renal elimination fraction QR = c1 R/CL, and the patient's individual creatinine clearance (c1cR) ratio, r (Appendix II): [Eq. 1]

The nonrenal elimination fractions (QNR) of more than 200 drugs were calculated by Dettli and coworkers,l14,24] and have been tabulated in the Swiss Pharmacopoeia since 1981.l 25 ] Furthermore, QNR can be determined from the data on the normal renal elimination fraction QR,n given in Martindale:[26]

The c1cR ratio, r, is itself defined as the ratio of the individual to the normal creatinine clearance:

In contrast to renal insufficiency, c1cR is considerably increased during the second and third trimester of pregnancy. There is a cyclic variation of endogenous creatinine clearance from 90 to 110 ml/min during the normal menstrual cycle.l27 ] However, at 12 weeks' gestation the mean c1cR is increased to about 130 ml/min and the mean pregnancy values during the second and third trimester are elevated at 140 to 150 ml/min, except for the last month, when c1 cR seems to decrease again - to about 120 ml/minJ5] Thus, we could assume that the c1cR ratio, r, is about 1.5 for the most part of pregnancy. As a result, clearance predictions in pregnancy involving drugs with predominantly renal elimination could be calculated by means of equation 1, when r is substituted for the corresponding clCR ratio in pregnancy, i.e. 1.5. In other words, the exClin. Drug Invest. 9 (4) 1995

Clearance Prediction and Dosage in Pregnancy

199

Table I. Patient characteristics and pharmacokinetic data during steady-state (metildigoxin)

Patient no.

GA (wks)

BW (kg)

Indication (maternallfetal)

Dosage" (mg/day)

CSS

(ng/ml)

cl (ml/min)

37 31 34 26 32 29 32 31

80 73 65 82 75 80 78 59

Maternal

2 3 4 5 6 7 8

0.4 0.4 0.4 0.4 0.6 0.4 0.5 0.4

1.04 1.15 1.30 1.20 1.62 1.20 1.25 0.97

194 176 156 169 187 169 203 209

Fetal Fetal Fetal Fetal Fetal Fetal Fetal

a Dosage = oral dosage per day. Abbreviations: BW = maternal bodyweight on admission; cI = drug clearance; CSS = additive plasma concentration of circulating metildigoxin plus digoxin at steady-state; GA = gestational age in weeks (wks) on admission.

pee ted drug clearance capacity in pregnancy QPr, defined as the ratio of pregnant to normal drug clearances (clfCL), can be determined using the following equation:

and cl=CL-QPr

[Eq.2a]

is the predicted drug clearance in pregnancy.

Materials and Methods Metildigoxin is well absorbed from the gastrointestinal tract, without relevant differences between the tablet formulation and oral solution, and partial demethylation to digoxin occurs in the liver. Bioavailability of unchanged metildigoxin after oral administration is 60% with respect to intravenous metildigoxin administration. However, this fraction does not comprise the total pharmacodynamic availability, since 13% of the oral metildigoxin is demethylated to digoxin during the first enterohepatic passage. Thus, based on the premise of equimolar pharmacodynamic equivalency of digoxin and metildigoxin, a total of 60 + 13 = 73% of the oral dose reaches the systemic circulation, i.e. F = 0.73 is the oral pharmacodynamic bioavailability.l 281 Metildigoxin and digoxin are nearly equimolar, with molecular weights of795.0 and 780.9, respec© Adis International Limited. All rights reserved.

tivelyp 61and are additive in serum immunoassays, i.e. the sum of their concentrations is measured.[ 281 Drug clearance values reported in clinical studies are often based on such additive drug concentration measurements. The same is true for our drug concentration measurements, which were performed with a commercially available radioimmunoassay with a sensitivity of 0.09 ngfml [Digoxin solid phase radioimmunoassay ('2SI) kit, Becton Dickinson Immunodiagnostics, New York, USA]. The correspondingly measured normal renal and nonrenal clearance values reported in the literature were 98.9 and 40 ml/min, respectively,[29-33 1 and the elimination half-life after withdrawal of maintenance therapy is about 60 hours.f3 4 - 361 Thus, for the purpose of our study, we assumed that the total normal body clearance, CL, is 140 ml/min, and: CL = CLNR + CLR = 40 mllmin + 100 mllmin. Consequently, the nonrenal elimination fraction is QNR = CLNRfCL = 0.29, which corresponds closely with the values of 0.26 and 0.25 calculated from oral and intravenous data, respectively.[28,37 1Thus, we could assume a nonrenal elimination fraction QNR of 0.3. (When QNR in equation 2 is substituted with 0.25 instead of 0.3, the difference in the corresponding clearance predictions is <2%.) Ten pregnant women received metildigoxin tablets, O.lmg each (Lanitop®, Boehringer MannClin. Drug Invest. 9 (4) 1995

Gonser et al.

200

heim, Mannheim, Germany) with a dosage interval of 12 hours. Trough drug levels were measured using the above method. In view of recent reports of endogenous digoxin-like immunoreactive substances in pregnancy, we monitored serum levels in patients number 4 to 8 before initiation of metildigoxin administration. No immunoreactivity was detected in maternal serum. In patients 1 to 3, treatment had already been started before admission (table I). Drug clearance, cl, was calculated using the formula: cl = F· Dosage/c ss (Dosage: oral dose per day) where c SS is the steady-state drug leveI.l38) Bioavailability F was assumed to remain constant and cSS was estimated from the mean value of 3 trough level measurements obtained after steady-state conditions have normally been reached, i.e. not before lO days of constant treatment. Two patients had to be excluded because birth occurred earlier. In order to evaluate the significance of the effect of pregnancy on metildigoxin clearance, we compared the mean of the clearance values, cl, observed in the remaining 8 patients with the normal nonpregnant value, CL, of 140 mllmin, using the I-sample t -test: [39) t = (mean - CL)/(SD/-vn) with n = 8. The test statistic t allows for the calculation of the probability P for obtaining the observed clearance values, cl, by chance, if there was no effect of pregnancy on metildigoxin clearance. Based on the t distribution with n - 1 = 7 degrees of freedom, a value of t>t7(0.05) = 2.365 corresponds to a 2-tailed value of p<0.05 , which is considered to indicate statistical significance, and [mean ± 2.365. SD/-V8] represents the 95% confidence interval for pregnant clearance values.[39) © Adis International Limited. All rights reserved.

Results Metildigoxin Clearance Measurements

Eight patients were treated with oral metildigoxin over a minimum of lO days plus the sampling period: 1 patient for a maternal indication and 7 for fetal indications. Dosage, steady-state plasma concentrations and calculated total clearance are given in table I. Drug clearance was 183.1 ± 18.6 ml/min (mean ± SD), which corresponds to a value of t =6.554 > 5.408 = t7(0.001) . This indicates that drug clearance, c\, was significantly increased (p
=0.28mg

This amount may also be predicted, as is shown in the following: The renal elimination fraction is the amount eliminated renally (Ae SS ), relative to the amount absorbed (F • Dosage) during 24 hours at steady-state. This ratio corresponds to the ratio of renal to total clearances in pregnancy:[41)

With clR/cl = QR/QPr = (QPr-QNR)/QPr (see Theory section), it follows that: Ae SS = F • Dosage(Qpr-QNR)/QPr = 0.73 • 0.5mg • (1.35-0.3)/1.35 = 0.284mg, which agrees well with 0.28mg, the amount recovered in urine. Clin. Drug Invest. 9 (4) 1995

Clearance Prediction and Dosage in Pregnancy

201

Table II. Predicted and reported drug clearances in pregnancy

Substance

_C_le_a_ra_n_ce_(:....m-::".,..m_in.!....)_ _ _ _ _ _ _ _ _ _ _ _ __ nonpregnant CL pregnant reported cl

Elimination parameters

aPr

ONR

predicted" cI

Ampicillin l221

394

613

571

0.1

1.45

Cefuroxime[231

198

282

290

0.07

1.465

Metildigoxin (present study)

140

183

189

0.3

1.35

Clearance predictions are based on equations 2 and 2a (see Theory section in text).

a

Abbreviations: CL = normal nonpregnant clearance; cl = pregnant clearance; ONR = nonrenal elimination fraction, data from Dettli[24I; = drug clearance capacity in pregnancy, calculated according to equation 2.

aPr

Clearance Predictions

For the second and third trimesters of pregnancy, clearance predictions for drugs with predominantly renal elimination may be based on the following estimate of the expected drug elimination capacity QPr (= cl/CL):

i.e. ampicillin clearance is predicted to be increased by 45% above the normal nonpregnant value CL: cl = 1.45 • 394 mllmin = 571 mllmin Cefuroxime: QNR = 0.07,[24] CL= 198 ml/min,[23] then:

[Eq.2] QPr = 0.07 + 0.93 • 1.5 = 1.465

This result, which is an extrapolation ofDeuli's clearance prediction approach, has already been derived and presented in the theory section. Here we apply this approach for clearance prediction in pregnancy to metildigoxin, and also to published pregnant and nonpregnant data for ampicillin and cefuroxime, in order to test the correspondence between predictions and real measurements (table Il): Metildigoxin: QNR = 0.3, CL = 140 ml/min (see Patients and Methods section), then: QPr = 0.3 + 0.7 • 1.5 = 1.35

Thus, drug clearance is predicted to be increased by about 35% above normal, and with equation 2a the predicted drug clearance, cl, is: cl = QPr· CL = 1.35 • 140 mllmin = 189 mllmin Ampicillin: QNR = 0.1,[24] CL = 394 ml/min,[22] then: QPr = 0.1 + 0.9· 1.5 = 1.45 © Adis International Limited. All rights reserved.

i.e. cefuroxime clearance is predicted to be increased by 46.5% above the normal CL: cl = 1.465 • 198 ml/min = 290 mllmin

Discussion Recent studies in pregnant women have indicated that the digoxin dosage should be increased in order to avoid drug levels falling below the therapeutic range.l 18 -20 ,42,43] The same holds for several B-Iactam antibiotics and also for aminoglycosides with predominantly renal elimination.l44 ] Ampicillin clearance, for instance, is known to be increased considerably during pregnancy[22,45] and during labour.[46] Our study shows a significant increase in metildigoxin/digoxin clearance during pregnancy. However, clearance variability was high and the evaluable number of patients was low. Nevertheless, since digoxin and metildigoxin are eliminated mainly by the kidneys, our study suggests that the increased clearance of these compounds is due to Clin. Drug Invest. 9 (4) 1995

202

the enhanced renal elimination, as indicated by the increased creatinine clearance in pregnancy. However, one study reported higher digoxin concentrations during the third trimester of pregnancy than during the postpartum period, in spite of higher digoxin renal clearance, higher clcR and higher 24-hour urine elimination of the drug during the third trimester compared with postpartum values.l47 ] Whether these contradictory results may be explained by endogenous digoxin-like immunoreactive substances, which have been recently found in pregnancy,[48.51] is not clear)52] In our study, steady-state drug levels, c Ss , were estimated from trough levels at steady-state. In principle, trough steady-state levels are lower than average steady-state levels. However, when the half-life is much longer than the dosage interval (metildigoxin/digoxin: 60/40 versus 12 hours), the trough steady-state level represents a good approximation ("" 94%) of the average steady-state level in I-compartment systems with intravenous bolus adrninistration.[53] Here, this approximation should be even better, because 4-compartmental distribution characteristics may be assumed for metildigoxin, with a pseudo-distribution equilibrium among tissues 12 hours after administration.[37] Dettli's approach for clearance prediction and dosage adjustment[54,55] has been of interest in obstetrics because his approach may be extrapolated to increased renal elimination capacity, as found in pregnancy. The metildigoxin clearance value, predicted by this extrapolated approach, agreed well with the corresponding result obtained in our clinical study. Furthermore, when the clearance predictions for ampicillin and cefuroxime, obtained by the same method, were compared with published pregnant data, good correspondence was also observed (table II). This suggests that the presented approach seems to be valid in the second and third trimesters of pregnancy for drugs with predominantly renal elimination. Thus, the presented clearance prediction approach using equation 2 provides a first estimate for dosage adjustment in pregnancy. © Adis International Limited. All rights reserved.

Gonser et al.

Drug therapy should be adjusted by increasing the maintenance dose in proportion to the predicted clearance in order to obtain the same target blood levels in pregnancy. However, this method, as with all other methods, is based upon certain assumptions, e.g. linearity of elimination kinetics or an unchanged nonrenal component, QNR, of drug clearance during pregnancy. The validity of these assumptions may be impaired, in particular by pregnancy-induced changes in drug metabolism. For this reason, only drugs with predominantly renal elimination can be considered and, if appropriate, drug monitoring should be taken into account for safety reasons and for further dosage adjustments. The fetal-placental unit and, after birth, the onset of lactation may have variable effects on pharmacokinetics.l I ,2,9,52] However, the absorption and bioavailability of most drugs that are given orally on a regular basis seem to be little affected by the changing gastrointestinal blood flow and the decreased intestinal motility, except during labour itsel0 2] On the other hand, other pregnancy-related factors, like increased blood volume and body mass, may affect maternal drug levels more profoundly and thus require additional dosage adjustments.

Appendix I: Extrapolation of Dosage Rules The average steady-state blood level, CSs, during multiple dosage (DIT) of a drug with linear elimination kinetics is a function of the dose D, the bioavailability F, the distribution volume Vd, the elimination rate constant K, and the dosage interval T:[56] CSS

= F. D/(K • Vd • T)

[Eq.3]

This function can be transformed into a noncompartmental expression,[38,53] given in capital letters to characterise normal or standard pharmacokinetic conditions [total body clearance (CL)]: CSS

= F • D/(CL. T)

[Eq.4] Clin. Drug Invest. 9 (4) 1995

Clearance Prediction and Dosage in Pregnancy

203

or given in lower case letters to characterise individual or specific pharmacokinetic conditions: CSS

= f • d/( cl • t)

[Eq.4a]

The latter expression is preferable for application in pregnancy, where kinetic parameters are physiologically changed and where a multicompartmental model may be more appropriate. Assuming that the same target blood level should be obtained: css =

C Ss,

i.e.

f· d/(cl • t) = F· D/(CL· T),

and that bioavailability remains unchanged (f = F), then for the individual drug clearance capacity, Q, it follows that:

Again, capital letters and lower case letters characterise normal standard and specific individual pharmacokinetics, respectively. Nonrenal drug clearance is assumed to be independent of renal function, i.e. cl NR = CLNR. Thus, the nonrenal elimination fraction, QNR, is a constant: [Eq. 6] Renal drug clearance is assumed to be proportional to endogenous clcR . Thus, the clcR ratio, defined as the ratio of the individual clcR to normal CLCR: r = clcR/CLCR, and the renal elimination capacity, defined as the ratio of the individual to normal renal drug clearances: clR/CLR, are changed to the same extent: [Eq.7]

Q = cl/CL = d • T/(D • t). Rearrangement with equation 5 yields: The generalised dosage rules for altered (reduced or increased) elimination capacity are now easily derived: Case J: dosage interval T, is kept constant: t=T then: d = D • Q (Rule 1), and Case 2: maintenance dose D, is kept constant: d=D then: t = T/Q (Rule 2).

Appendix II: Extrapolation of Clearance Prediction Total drug clearance is the sum of nonrenal and renal clearances, in normal as well as in altered renal function: [Eq.5] and [Eq.5a] © Adis International Limited. All rights reserved.

[Eq.8] The individual drug clearance capacity, Q, is defined as the ratio of the patient's individual to normal drug clearances: Q = cl/CL. Then with equations 5a and 8 it follows that:

Q = cl/CL = clNR/CL + clR/CL = clNR/CL + (CL-CL NR ) • r/CL, and with equation 6 yields: [Eq. 1]. QED

References I. Nau H, Mirkin BL. Fetal and maternal clinical pharmacology. In: Speight TM, Avery GS, editors. Avery's drug treatment. 3rd ed. Auckland: Adis Press, 1987: 79-117 2. Reynolds F. Pharmacokinetics. In: Hytten F, Chamberlain G, editors. Clinical physiology in obstetrics. 2nd ed. Oxford: Blackwell, 1991: 224-41 3. Chesley LC. Renal functional changes in normal pregnancy. Clin Obstet Gynecol 1960; 3: 349-63

Clin. Drug Invest. 9 (4) 1995

204

4. Davison JM, Dunlop W. Renal hemodynamics and tubular function in normal human pregnancy. Kidney Int 1980; 18: 152-61 5. Davison JM , Dunlop W, Ezimokhai M. 24-hour creatinine clearance during the third trimester of normal pregnancy. Br J Obstet Gynaecol 1980; 87: 106-9 6. Parker WA. Effects of pregnancy on pharmacokinetics. In: Benet LZ, Massoud N, Gambertoglio JG , editors. Pharmacokinetic basis for drug treatment. New York: Raven Press, 1984: 249-68 7. Sturgiss SN, Dunlop W, Davison JM. Renal haemodynamics and tubular function in human pregnancy. Baillieres Clin Obstet Gynaecol 1994; 8: 209-34 8. Cummings AJ. A survey of pharmacokinetic data from pregnant women. Clin Pharmacokinet 1983; 8: 344-54 9. Krauer B, Krauer F. Drug kinetics in pregnancy. Clin Pharmacokinet 1977; 2: 167-81 10. Dvorchik BH. Drug disposition during pregnancy. Bioi Res Preg 1982; 3: 129-37 II . Eadie MJ, Lander CM , Tyrer JH . Plasma drug level monitoring in pregnancy. Clin Pharmacokinet 1977; 2: 427-36 12. Dettli L, Spring P, Ryter S. Multiple dose kinetics and drug dosage in patients with kidney disease. Acta Pharmacol Toxico11971 ; 29 Suppl. 3: 211-24 13. Detlli L. Drug dosage in renal di sease. Clin Pharmacokinet 1976; I: 126-34 14. Dettli L. Elimination kinetics and dosage adjustment of drugs in patients with kidney disease. Progress in Pharmacology Vol. I, (4). New York: Fischer, 1977: 1-34 15. Golichowski AM, Cal dell R, Hartsough A, et al. Pharmacologic cardioversion of intrauterine supraventricular tachycardia. A case report. J Reprod Med 1985; 30: 139-44 16. Kleinman CS, Copel JA, Weinstein EM, et al.ln utero diagnosis and treatment of fetal supraventricular tachycardia. Semin Perinatol 1985; 9: 113-29 17. Maxwell DJ, Crawford DC, Curry PVM, et al. Obstetric importance, diagnosis, and management of fetal tachycardias. BMJ 1988; 297: 107-10 18. Rotmensch HH, Elkayam U, Frishman W. Antiarrhythmic drug therapy during pregnancy. Ann Intern Med 1983; 98: 487-97 19. Rotmensch HH, Rotmensch S, Elkayam U. Management of cardiac arrhythmias during pregnancy. Current concepts. Drugs 1987; 33: 623-33 20. Stewart PA, Wladimiroff Jw. Cardiac tacharrhythmias in the fetus: diagnosis, treatment and prognosis. Fetal Ther 1987; 2: 7-16 21. Wladimiroff JW, Stewart PA . Treatment of fetal cardiac arrhythmias. Br J Hosp Med 1985; 9: 134-40 22. Philipson A. Pharmacokinetics of ampicillin during pregnancy. J Infect Dis 1977; 136: 370-6 23. Philipson A, Stiernstedt G. Pharmacokinetics of cefuroxime in pregnancy. Am J Obstet Gynecol 1982; 142: 823-8 24. Dettli L. The kidney in pre-clinical and clinical pharmacokinetics. Jpn J Clin Pharmacol Ther 1984; 15: 241-54 25. Neugebauer J, editor. Compendium Suisse des Medicaments 1981; Basel: Documed, 1981 26. Reynolds JEF, editor. Martindale. The extra pharmacopoeia. London: The Pharmaceutical Press, 1993 27. Davison JM , Noble MCB. Serial changes in 24 hour creatinine clearance during normal menstrual cycles and the first trimester of pregnancy. Br J Obstet Gynaecol 1981 ; 88: 10-7 28. Hinderling PH, Garrett ER, Wester RC. Pharmacokinetics of B-methyldigoxin in healthy humans II: oral studies and bioavailability. J Pharm Sci 1977; 66: 314-25

© Adis International Limited. All rights reserved.

Gonser et al.

29. Betzien G, Dietmann K, Schaumann W. Absorption, renal and extrarenal clearance of digoxin [in German]. Herz Kreisl 1980; 12: 115-20 30. Haasis R, Larbig D. Glycoside concentration in the serum of elderly patients after taking B-methyldigoxin, B-acetyldigoxin and digoxin [in German]. Geriatrie 1977; 2: 65-73 31. Keller F, Blumenthal HP, Maertin K, et al. Overall pharmacokinetics during prolonged treatment of healthy volunteers with digoxin and B-methyldigoxin. Eur J Clin Pharmacol 1977; 12: 387-92 32. Marinow J, Olcay A, Schaumann W, et al. Serum glycoside concentrations after single or repeated intravenous doses of B-methyl-digoxin and digoxin. Eur J Clin Pharmacol 1977; II : 213-8 33. Schaumann W, Kaufmann B. Resorption, distribution et elimination des glucosides digitaliques. Actualit':s Pharmacol 1979; 31: 143-68 34. Bel z GG, Kleeberg UR. Plasma half life of B-methyl-digoxin following repetitive application in man. Klin Wochenschr 1975; 53: 491-2 35. Haasis R, Larbig D, Klenk K. Cardiac effects and glycoside concentrations in serum and urine after oral administration of B-methyl-digoxin to healthy individuals [in German]. Klin Wochenschr 1975 ; 53: 529-33 36. Rietbrock N, Kuhlmann J , Guggenmos J, et al. Bioavailability and pharmacokinetics of B-methyldigoxin after multiple oral and intravenous doses. Eur J Clin Pharmacol 1976; 9: 373-9 37. Hinderling PH, Garrett ER, Wester RC. Pharmacokinetics of B-methyldigoxin in healthy humans I: intravenous studies. J Pharm Sci 1977; 66: 242-53 38. Benet LZ, Mitchell JR, Sheiner LB. Pharmacokinetics: The dynamics of drug absorption, distribution, and elimination. In: Gilman AG, Rail TW, Nies A, et aI. , editors. Goodman and Gilman '5 The pharmacological basis of therapeutics. 8th ed. New York : Pergamon Press, 1990: 3-32 39. Altman DG. Practical statistics for medical research. London : Chapman and Hall, 1991: 162-71 , 183-5 40. Petrie A. Lecture notes on medical statistics, 2nd ed. Oxford: Blackwell, 1987: 50-1,82-3 41. Klotz U. Klinische Pharmakokinetik. Stuttgart: Gustav Fischer Verlag, 1984 42. Rogers MC, Willerson JT, Goldblatt A, et al. Serum digoxin concentrations in the human fetus , neonate and infant. N Engl J Med 1972; 287: 1010-3 43 . Pitkin RM . Drugs in pregnancy. In: Quilligan EJ, Kretchmer N, editors. Fetal and maternal medicine . New York: Wiley, 1980: 385-402 44. Philipson A. Pharmacokinetics of antibiotics in pregnancy and labour. Clin Pharmacokinet 1979; 4: 297-309 45. Chamberlain A, White S, Bawdon R, et al. Pharmacokinetics of ampicillin and sulbactam in pregnancy. Am J Obstet Gynecol 1993; 168: 667-73 46. Hirsch HA. Transfer of various antibiotics into the intrauterine compartments during steady state in the mother. Bioi Res Preg 1980; I: 124-7 47. Luxford AME, Kellaway GSM. Pharmacokinetics of digoxin in pregnancy. Eur J C1in Pharmacol 1983; 25: 117-21 48. Graves SW, Valdes R, Brown BA, et al. Endogenous digoxinimmunoreactive substance in human pregnancies. J Clin Endocrinol Metab 1984; 58: 748-51 49. Hicks JM, Brett EM. Falsely increased digoxin concentrations in sample from neonates and infants. Ther Drug Monit 1984; 6: 461-4

Clin. Drug Invest. 9 (4) 1995

Clearance Prediction and Dosage in Pregnancy

50. Koren G, Farine D, Maresky D, et al. Significance of endogenous digoxin-like substance in infants and mothers. Clin Pharmacol Ther 1984; 36: 759-64 51. Smith RL. Effect of digoxin-like immunoreactive substances on the 'Dac-Cel' digoxin assay. Clin Chern 1987; 33: 1697 52. Mitani GM, Steinberg I, Lien EJ, et al. The pharmacokinetics of antiarrhythmic agents in pregnancy and lactation. Clin Pharmacokinet 1987; 12: 253-91 53. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, 1982: 132-44, 385-93, 409-17 54. Gonser M. Transplacental digitalisation of the fetus - proposal of loading and maintenance dose calculations based on maternal weight and creatinine clearance [abstract]. Naunyn Schmiedebergs Arch Pharmacol 1988; 337 Suppl.: R4

© Adis International Limited. All rights reserved.

205

55. Gonser M, Dietl J, Pfeiffer KH, et al. Evaluation of fetal heart rate artifacts, haemodynamics and digoxin treatment in fetal tachyarrhythmia by Doppler measurement of fetal blood flow - case report of a pre-excitation syndrome. J Perinat Med 1989; 17: 411-6 56. Wagner JG, Northam 11, Alway CD, et al. Blood levels of drug at the equilibrium state after multiple dosing. Nature 1965; 207: 1301-2

Correspondence and reprints: Dr med . M. Gonser, Universitats-Frauenklinik, Schleichstrasse 4, 0-72076 Tiibingen, Germany.

Clin. Drug Invest. 9 (4) 1995