Clinical Drug Investigation

, Volume 9, Issue 4, pp 197–205 | Cite as

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
  • P. Kahle
Original Research Clinical Pharmacokinetics


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 = cl/CL), and can be calculated by the following equation: QPr= Qnr+ (1-Qnr) · 1.5, where Qnr is 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 non-pregnant 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 ml/min). Clearance predictions for ampicillin and cefuroxime were performed using published data, and again close agreement was found between predicted and published clearance values.


Adis International Limited Digoxin Cefuroxime Drug Invest Drug Clearance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    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: 79–117Google Scholar
  2. 2.
    Reynolds F. Pharmacokinetics. In: Hytten F, Chamberlain G, editors. Clinical physiology in obstetrics. 2nd ed. Oxford: Blackwell, 1991: 224–41Google Scholar
  3. 3.
    Chesley LC. Renal functional changes in normal pregnancy. Clin Obstet Gynecol 1960; 3: 349–63CrossRefGoogle Scholar
  4. 4.
    Davison JM, Dunlop W. Renal hemodynamics and tubular function in normal human pregnancy. Kidney Int 1980; 18: 152–61PubMedCrossRefGoogle Scholar
  5. 5.
    Davison JM, Dunlop W, Ezimokhai M. 24-hour creatinine clearance during the third trimester of normal pregnancy. Br J Obstet Gynaecol 1980; 87: 106–9PubMedCrossRefGoogle Scholar
  6. 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: 249–68Google Scholar
  7. 7.
    Sturgiss SN, Dunlop W, Davison JM. Renal haemodynamics and tubular function in human pregnancy. Baillieres Clin Obstet Gynaecol 1994; 8: 209–34PubMedCrossRefGoogle Scholar
  8. 8.
    Cummings AJ. A survey of pharmacokinetic data from pregnant women. Clin Pharmacokinet 1983; 8: 344–54PubMedCrossRefGoogle Scholar
  9. 9.
    Krauer B, Krauer F. Drug kinetics in pregnancy. Clin Pharmacokinet 1977; 2: 167–81PubMedCrossRefGoogle Scholar
  10. 10.
    Dvorchik BH. Drug disposition during pregnancy. Biol Res Preg 1982; 3: 129–37Google Scholar
  11. 11.
    Eadie MJ, Lander CM, Tyrer JH. Plasma drug level monitoring in pregnancy. Clin Pharmacokinet 1977; 2: 427–36PubMedCrossRefGoogle Scholar
  12. 12.
    Dettli L, Spring P, Ryter S. Multiple dose kinetics and drug dosage in patients with kidney disease. Acta Pharmacol Toxicol 1971; 29 Suppl. 3: 211–24Google Scholar
  13. 13.
    Dettli L. Drug dosage in renal disease. Clin Pharmacokinet 1976; 1: 126–34PubMedCrossRefGoogle Scholar
  14. 14.
    Dettli L. Elimination kinetics and dosage adjustment of drugs in patients with kidney disease. Progress in Pharmacology Vol. 1, (4). New York: Fischer, 1977: 1–34Google Scholar
  15. 15.
    Golichowski AM, Caldell R, Hartsough A, et al. Pharmacologic cardioversion of intrauterine supraventricular tachycardia. A case report. J Reprod Med 1985; 30: 139–44PubMedGoogle Scholar
  16. 16.
    Kleinman CS, Copel JA, Weinstein EM, et al. In utero diagnosis and treatment of fetal supraventricular tachycardia. Semin Perinatol 1985; 9: 113–29PubMedGoogle Scholar
  17. 17.
    Maxwell DJ, Crawford DC, Curry PVM, et al. Obstetric importance, diagnosis, and management of fetal tachycardias. BMJ 1988; 297: 107–10PubMedCrossRefGoogle Scholar
  18. 18.
    Rotmensch HH, Elkayam U, Frishman W. Antiarrhythmic drug therapy during pregnancy. Ann Intern Med 1983; 98: 487–97PubMedGoogle Scholar
  19. 19.
    Rotmensch HH, Rotmensch S, Elkayam U. Management of cardiac arrhythmias during pregnancy. Current concepts. Drugs 1987; 33: 623–33PubMedCrossRefGoogle Scholar
  20. 20.
    Stewart PA, Wladimiroff JW. Cardiac tacharrhythmias in the fetus: diagnosis, treatment and prognosis. Fetal Ther 1987; 2: 7–16PubMedCrossRefGoogle Scholar
  21. 21.
    Wladimiroff JW, Stewart PA. Treatment of fetal cardiac arrhythmias. Br J Hosp Med 1985; 9: 134–40Google Scholar
  22. 22.
    Philipson A. Pharmacokinetics of ampicillin during pregnancy. J Infect Dis 1977; 136: 370–6PubMedCrossRefGoogle Scholar
  23. 23.
    Philipson A, Stiernstedt G. Pharmacokinetics of cefuroxime in pregnancy. Am J Obstet Gynecol 1982; 142: 823–8PubMedGoogle Scholar
  24. 24.
    Dettli L. The kidney in pre-clinical and clinical pharmacokinetics. Jpn J Clin Pharmacol Ther 1984; 15: 241–54CrossRefGoogle Scholar
  25. 25.
    Neugebauer J, editor. Compendium Suisse des Médicaments 1981; Basel: Documed, 1981Google Scholar
  26. 26.
    Reynolds JEF, editor. Martindale. The extra pharmacopoeia. London: The Pharmaceutical Press, 1993Google Scholar
  27. 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: 10–7PubMedCrossRefGoogle Scholar
  28. 28.
    Hinderling PH, Garrett ER, Wester RC. Pharmacokinetics of ß-methyldigoxin in healthy humans II: oral studies and bioavailability. J Pharm Sci 1977; 66: 314–25PubMedCrossRefGoogle Scholar
  29. 29.
    Betzien G, Dietmann K, Schaumann W. Absorption, renal and extrarenal clearance of digoxin [in German]. Herz Kreisl 1980; 12: 115–20Google Scholar
  30. 30.
    Haasis R, Larbig D. Glycoside concentration in the serum of elderly patients after taking ß-methyldigoxin, ß-acetyldigoxin and digoxin [in German]. Geriatrie 1977; 2: 65–73Google Scholar
  31. 31.
    Keller F, Blumenthal HP, Maertin K, et al. Overall pharmacokinetics during prolonged treatment of healthy volunteers with digoxin and ß-methyldigoxin. Eur J Clin Pharmacol 1977; 12: 387–92PubMedCrossRefGoogle Scholar
  32. 32.
    Marinow J, Olcay A, Schaumann W, et al. Serum glycoside concentrations after single or repeated intravenous doses of ß-methyl-digoxin and digoxin. Eur J Clin Pharmacol 1977; 11: 213–8PubMedCrossRefGoogle Scholar
  33. 33.
    Schaumann W, Kaufmann B. Résorption, distribution et élimination des glucosides digitaliques. Actualités Pharmacol 1979; 31: 143–68Google Scholar
  34. 34.
    Belz GG, Kleeberg UR. Plasma half life of ß-methyl-digoxin following repetitive application in man. Klin Wochenschr 1975; 53: 491–2PubMedCrossRefGoogle Scholar
  35. 35.
    Haasis R, Larbig D, Klenk K. Cardiac effects and glycoside concentrations in serum and urine after oral administration of ß-methyl-digoxin to healthy individuals [in German]. Klin Wochenschr 1975; 53: 529–33PubMedCrossRefGoogle Scholar
  36. 36.
    Rietbrock N, Kuhlmann J, Guggenmos J, et al. Bioavailability and pharmacokinetics of ß-methyldigoxin after multiple oral and intravenous doses. Eur J Clin Pharmacol 1976; 9: 373–9CrossRefGoogle Scholar
  37. 37.
    Hinderling PH, Garrett ER, Wester RC. Pharmacokinetics of ß-methyldigoxin in healthy humans I: intravenous studies. J Pharm Sci 1977; 66: 242–53PubMedCrossRefGoogle Scholar
  38. 38.
    Benet LZ, Mitchell JR, Sheiner LB. Pharmacokinetics: The dynamics of drug absorption, distribution, and elimination. In: Gilman AG, Rall TW, Nies A, et al., editors. Goodman and Gilman’s The pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990: 3–32Google Scholar
  39. 39.
    Altman DG. Practical statistics for medical research. London: Chapman and Hall, 1991: 162–71, 183–5Google Scholar
  40. 40.
    Petrie A. Lecture notes on medical statistics, 2nd ed. Oxford: Blackwell, 1987: 50–1, 82–3Google Scholar
  41. 41.
    Klotz U. Klinische Pharmakokinetik. Stuttgart: Gustav Fischer Verlag, 1984Google Scholar
  42. 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: 1010–3PubMedCrossRefGoogle Scholar
  43. 43.
    Pitkin RM. Drugs in pregnancy. In: Quilligan EJ, Kretchmer N, editors. Fetal and maternal medicine. New York: Wiley, 1980: 385–402Google Scholar
  44. 44.
    Philipson A. Pharmacokinetics of antibiotics in pregnancy and labour. Clin Pharmacokinet 1979; 4: 297–309PubMedCrossRefGoogle Scholar
  45. 45.
    Chamberlain A, White S, Bawdon R, et al. Pharmacokinetics of ampicillin and sulbactam in pregnancy. Am J Obstet Gynecol 1993; 168: 667–73PubMedGoogle Scholar
  46. 46.
    Hirsch HA. Transfer of various antibiotics into the intrauterine compartments during steady state in the mother. Biol Res Preg 1980; 1: 124–7Google Scholar
  47. 47.
    Luxford AME, Kellaway GSM. Pharmacokinetics of digoxin in pregnancy. Eur J Clin Pharmacol 1983; 25: 117–21PubMedCrossRefGoogle Scholar
  48. 48.
    Graves SW, Valdes R, Brown BA, et al. Endogenous digoxinimmunoreactive substance in human pregnancies. J Clin Endocrinol Metab 1984; 58: 748–51PubMedCrossRefGoogle Scholar
  49. 49.
    Hicks JM, Brett EM. Falsely increased digoxin concentrations in sample from neonates and infants. Ther Drug Monit 1984; 6: 461–4PubMedCrossRefGoogle Scholar
  50. 50.
    Koren G, Farine D, Maresky D, et al. Significance of endogenous digoxin-like substance in infants and mothers. Clin Pharmacol Ther 1984; 36: 759–64PubMedCrossRefGoogle Scholar
  51. 51.
    Smith RL. Effect of digoxin-like immunoreactive substances on the ‘Dac-Cel’ digoxin assay. Clin Chem 1987; 33: 1697PubMedGoogle Scholar
  52. 52.
    Mitani GM, Steinberg I, Lien EJ, et al. The pharmacokinetics of antiarrhythmic agents in pregnancy and lactation. Clin Pharmacokinet 1987; 12: 253–91PubMedCrossRefGoogle Scholar
  53. 53.
    Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, 1982: 132–44, 385–93, 409–17Google Scholar
  54. 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.: R4Google Scholar
  55. 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: 411–6PubMedCrossRefGoogle Scholar
  56. 56.
    Wagner JG, Northam JI, Alway CD, et al. Blood levels of drug at the equilibrium state after multiple dosing. Nature 1965; 207: 1301–2PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • M. Gonser
    • 1
  • P. Stoll
    • 1
  • P. Kahle
    • 1
  1. 1.Department of Obstetrics and GynaecologyUniversity Hospital of TübingenTübingenGermany

Personalised recommendations