- Email: [email protected]
A loading-dose infusion scheme for intravenous tocolysis with ritodrine: a pilot study
119
Eur. J. Obstet. Gynecol. Reprod Biol., 26 (1987) 119-126 Elsevier
ELJO 00521
A loading-dose infusion scheme for intravenous tocolysis with ritodrine: a pilot study C.A.G. Holleboom
‘, J.M.W.M.
Merkus
’ and L.W.M.
van Elferen
2
’ Department of Obstetrics and Gynecology, Maria Hospital Tilburg, The NetherIan& and 2 Department of Clinical Research Duphar Nederland BV, The Netherlands Accepted for publication 14 May 1987
A loading-dose infusion scheme for intravenous ritodrine therapy was tested in twelve patients with preterm labour. We started with a rather high (386 ~g/min) infusion rate, but the moment tocolysis was reached this infusion rate was reduced to a level needed to maintain the plasma concentration then found. Plasma samples of ritodrine were taken the moment tocolysis was reached and in the steady state, and compared with each other and with expected and calculated plasma concentrations. In the dynamic loading phase we found a half-life for ritodrine of 1 h. This half-life of 1 h can be explained by cumulation of ritodrine in the central compartment and is therefore called cumulation t,,,. In developing an infusion scheme with a loading dose for ritodrine, this cumulation t,,, of 1 h should be taken into account. Cumulation t ,,*;
Ritodrine plasma level
Introduction
Beta-2-sympathomimetics are potent drugs designed to reduce uterine activity. They are used worldwide in preventing preterm labour [l]. Usually the initial therapy is started intravenously [1,8]. All currently applied intravenous dose regimens are empirical, and a rational dosage scheme based on plasma concentrations and related to the pharmacokinetic properties of the beta-mimetic drug has not been developed until now. Correspondence: C.A.G. Holleboom, Department of Obstetrics and Gynecology, Deelenlaan 5, 5042 AD Tilburg, The Netherlands.
0028-2243/87/%03.50
Maria Hospital, Dr
0 1987 Elsevier Science Publishers B.V. (Biomedical Division)
120 TABLE I Ritodrine dosage protocol Initial infusion rate: 386 pg/min tocolysis after
reduce dosage to
o-45 mill 46 min-1 h 15 min lh16rnin-2h 2h-3h 3h-4h 4 h-6 h 6 h-10 h
97 Pgmn 144 ag/min 193 pg/min 241 pg/min 288 pg/min 336 &min 386 &min
Initially a parenteral fixed dose regimen was applied [13], but this has now largely been replaced by an incremental dosage scheme [l]. With this incremental dosage scheme a low initial dose is increased every lo-15 minutes with a fixed dose until uterine contractions stop or unacceptable side-effects develop. In general, at cessation of uterine activity the infusion rate is maintained. However, due to the pharmacokinetic properties of these drugs the plasma concentration will subsequently increase above the level reached at that time, leading to more frequent and serious dose-related side-effects [lo]. To avoid this overdose we tried to develop an infusion scheme starting with a rather high intravenous infusion rate of ritodrine (386 pg/rnin) until contractions disappeared, subsequently reducing the infusion rate to the level needed to maintain the concentration reached at that time. To test the validity of this infusion scheme we compared plasma concentrations found at the moment of tocolysis with plasma concentrations in the steady state. An abstract of this study has been published [6]. Phannacokinetic
background
The rise of the plasma level of a drug, when given by intravenous infusion, is shown in Fig. 1. After the start of the infusion the concentration rises until the steady state is reached. The height of the plasma level depends on the pharmacokinetic properties of the drug, such as its distribution volume (I’,) and its elimination rate constant (K,) as well as the infusion rate (R) and the lapse of time after the start of the infusion (t). The blood concentration C, (mg/ml) can be expressed by means of the following equation [51:
c,=
&D
e (1 - emKer)
The elimination rate constant is related to the drug half-life (ti,z) according to K = 0.693 e h/2
121
Fig. 1. Build-up of the blood level of a drug given by intravenous CS, = steady-state concentration; R = infusion rate.
infusion.
f,,* = half-life
of the drug;
In the steady state, t is large as compared to t,,*, which gives:
In this steady-state situation the concentration of the drug (C,,) is determined by the infusion rate (R) and the clearance (V,K,). The above is valid for drugs with first-order kinetics (the majority) and an open one-compartment model. Fqn. 1 can be turned into: C, = <,,(l - e-o.693.$) If, for instance, the time after the start of the infusion (t) is equal to t1,2 of the infused drug c
, the corresponding
plasma concentration
is:
‘-
From this it can be calculated that after one t,,,, 50% of the final steady state is reached; after two t,,, it is 75%; after three t,, 87.5%, etc. Similarly, the steady-state concentration (about 96.9%) is almost reached after a period of approximately 5-times the half-life of the drug. Should this model be applied to the inhibition of labor with beta-2-sympathomimetics, the desirable infusion rate can be determined from the uterine activity and the duration of the infusion. Patients and procedures Twelve healthy patients in preterm labour, mean gestational age 208 f 30 (SD) days (see Table II), were treated intravenously with ritodrine according to the protocol after giving their informed consent for participation in the study. Adequate plasma samples could not be obtained from three patients. Preterm labor was defined as more than 10 uterine contractions in 30 min before the 36th week of
122 TABLE II Characteristics of the 12 patients (means f S.D.) n Age 01) Weight (kg) Height (cm) Gestational age (days) Range Bishop score Tocolysis index (Baumgarten)
28.6+ 4.3 5&l* 7.6 167 f 8.1 208 f 30 159 f241 3.5* 1.7 2.6$- 1.2
12 11 10 10 11 11
gestation. All patients were healthy and none of them had used beta-mimetics during pregnancy. Besides ritodrine and bed-rest no other treatment had been given. Fifty mg ritodrine (5 ml) were dissolved in 45 ml 5% glucose (1 mg/ml) and administered by an infusion pump (Razel, type A99, flow-rate 1.43-30 pi/h). The infusion was started at a level of 386 pg/min ritodrine and reduced according to the protocol when no contractions were observed for more then 15 min (see protocol). This lower dosage was unchanged for at least 48 h. The infusion scheme is based on the reported elimination half-life (ti& for ritodrine of 2 h [4]. Blood samples were taken both when tocolysis was reached or 2 h after starting the infusion (C,) and in the expected steady state (C,,) (20-24 h after reducing the infusion rate). Ten ml of blood were taken from the cubital vein opposite the infusion arm, heparinized and centrifuged (300 rpm) and the supematant was stored at -20°C until the time of analysis. The ritodrine plasma levels were measured at the Duphar Research Laboratories, Weesp, The Netherlands, by the radioimmunoassay method, previously published by Gandar et al. [4] and Thomas et al. [12]. No information on the infusion rate used was available in the laboratory. The sensitivity of this RIA is 0.1 ng/ml, cross-reaction with ritodrine metabolites 0.2% and coefficient of variations 4.1%. Pharmacokinetic calculations were done with the above-mentioned formulae. Statistical evaluation was performed with Pearson correlation and Wilcoxon matched-pairs signed-ranks tests. A p-value of 0.05 or less is regarded as being statistically significant. Results
All patients tolerated the infusion scheme well and no serious side-effects compelling us to change or stop the infusion rate developed. Changes in maternal and fetal heart rate and blood pressure are given in Table III. A change of more than 5 mmHg in systolic and diastolic blood pressure and 10 mmHg in pulse pressure with pretreatment values was regarded as being a significant difference. In the maintenance period no dose adjustments were necessary because uterine contractions did not recur. Tocolysis was achieved in all 12 patients within 8 h and in 9 out of 12 patients within 1.30 h (Table IV). This means that to maintain tocolysis 9 out of 12 patients required less than 200 pg/min ritodrine.
123 TABLE
III
Pretreatment and maximum values during treatment in the first 6 h of maternal heart rate (MHR), fetal heart rate (FHR), systolic blood pressure, diastolic blood pressure and pulse pressure in relation to time of occurrence after starting the infusion (I,,). Pretreatment (n = 12) MHR (beats/mm) mean f SD range FHR (beats/mm) meanfSD range Systolic BP (mmHg) mean f SD range Pulse pressure (mmHg) mean 5 SD range Diastolic BP (mmHg) mean f SD range Dose adjustment mean * SD range a Significantly b Significantly
During
first 6 h of treatment
max. values
t max Win)
fl9*17 60-116
126+20 80-150
=
52k37 5-120
144*13 120-160
168k15 140-200
a
82+64 15-240
124k 15 105-155
140*14 120-170
=
20b*11 5-30
46*11 30-65
68&12a 50-85 min. values 6Ok9 a 40-75
78k9 60-95
36 bf22 10-90 56+32 15-120 124+151 13-480
different from pretreatment (p < 0.005). before dose adjustment (p < 0.05).
With the measured plasma concentrations in the starting phase (C,) and steady(Table V). This state concentrations (C,,) a t,,, of 50 f 20 min was calculated half-life of 50 f 20 min is not the same as the elimination t,,, of 2 h used in our
TABLE
IV
Time elapse before Patient 1 2 3 4 5 6 7 8 9 10 11 12
No.
tocolysis
and dose adjustments
Tocolysis 13 25 29 33 36 1 hll 1 h36 3h 5 8h 1 h30 45 6 h 20
reached
after (min)
Dosage 97 97 97 97 97 144 193 241 386 193 97 336
to ( pg/min)
124 TABLE
V
Concentration at moment of tocolysis (C,), measured steady-state concentration (C,,), calculated steady-state concentration for tt,s = 2 h (C,,: t1,2= 2 h), calculated steady-state concentration for t t,r = 1 h (C,, : Q = 1 h) and cumulation 1,,, Patient No.
C, (ng/mU
1 2 3 4 5 6 7 8 9 MeanfSD
22 35 100 37 64 47 96 84 a 89 a 64f29
Cumulation q
C,
Calculated CSS:t,,,=l
(ng@)
(ng/nQ
(ng/mU
(mm)
78 66 163 54 86 53 112 105 126 94k36
34 43 50 32 24 34 71 51 98 49&23
40 36 88 30 47 32 71 70 97 57k25
50 74 29 65 23 67 59 21 63 5Ok20
Calculated C,, : 11~2 =
Measured 2 h
h
a Plasma samples taken 2 h after start of the infusion.
dosage scheme. This is probably a result of distribution from central to peripheral compartments and elimination processes. The t,,, reflects the pharmacodynamics of ritodrine in the loading phase of the infusion and is called by us the cumulation t,,,. The cumulation t,,, is the time needed after starting the infusion to reach half of the steady-state concentration without changing the infusion rate. As a result of plasma concentrations in the steady state this discrepancy in t,,, the measured (C,, = 49 f 23 ng/ml) were lower than the calculated C,, for t,,, = 2 h (see Table
140- Css talc RITODRINE
nglml
i 120-
-1-1-1-1 20
40 60 80 100 Css measured nglml
Fig. 2. Correlation between measured and calculated steady-state concentrations
for t1,2 = 1 h.
125
V). Comparison of calculated G, for h/2 = 1 hour with measured C,, revealed a good correlation. Correlation coefficient r = 0.81 (Pearson), significance p < 0.01 (Fig. 2). Discussion
The incremental dosage scheme used for intravenous tocolysis with beta-Zmimetits leads to overdose (Fig. 3). This is inherent in the scheme, because the contractions disappear before the steady-state concentration for that infusion rate is reached. It is better to reduce an initially fixed infusion rate to a dose level needed to maintain the effective concentration reached at that moment [7,10,11]. Ingels et al. [7] found steady-state concentrations of ritodrine after 2 h of infusion instead of the expected 6-8 h; Post [9] also observed this phenomenon. This is a consequence of cumulation of ritodrine in the central compartment. We studied an infusion scheme for ritodrine based on the reported half-life of 2 h [4]. Evaluating the results the cumulation t,,, was 50 f 20 min rather than the . . . reported elumnation t,,, of 2 h. This explains the difference in calculated and measured steady-state concentrations and in effective and measured steady-state concentrations. We observed interindividual differences in cumulation t,,, (21-74 min) which could have been due to individual differences in metabolism. The influence of pregnancy on ritodrine metabolism is not completely clear. Changes in liver metabolism, renal clearance, compartment and volume enlargement all play a role [2]. The infusion scheme used in our study takes these inter-individual differences into account: the infusion rate is reduced after contractions have disappeared and not after a fixed time. The degree to which the infusion rate is reduced is based on the pharmacokinetic considerations mentioned above. Further studies are needed in order to conclude whether reduction of the infusion rate with a scheme based on accumulation I,,~ = 1 h is feasible. Besides the lower risk of an excessively high plasma concentration, another advantage of the infusion scheme studied is that fewer dose adjustments are
n.
css
.
c:T______ !
plasma
level
needed
for tocdysis
Fig. 3. Overdose given after tocolysis is achieved at time A. C, = plasma concentration with infusion rate R. C,, = steady-state concentration reached with infusion rate R.
reached
at time A
126
necessary (only to reduce the infusion rate at time of tocolysis), which also leads to fewer side-effects. Side-effects depend not only on the absolute concentration of ritodrine; the rate of change in the infusion rate or drug concentration may be more important [3]. Finally, by using a high loading dose, effective plasma concentrations are achieved more rapidly than with the incremental dosage scheme, so the intended effect (tocolysis) can be expected earlier. Conclusions The proposed dosage scheme for intravenous ritodrine is in practice well-accepted by patients and needs very few dose adjustments. Instead of the reported elimination r,,, of 2 h a cumulation t,,z of 1 h should be used in developing a loading dose infusion scheme. This infusion scheme makes it possible to reach and maintain the minimal effective dosage in the individual patient. A new study with an infusion scheme based on the cumulation t,,, of 1 h is in progress. Acknowledgements We wish to thank L.W. de Zoete of the Duphar Company, Weesp, The Netherlands, for the determination of the ritodrine plasma concentrations by the RIA methodology. References 1 Barden TP, Peter JB, Merkatz IR. Ritodrine hydrochloride: A beta-mimetic agent for use in preterm labor. Obstet Gynecol 1980;56:1-6. 2 Bogaert MC, Thiery M. Phannacokinetics and pregnancy. Eur J Obstet Gynecol Reprod Biol 1983;16:229-235. 3 Caritis SW, Lin LS, Wong LK Pharmacodynamics of ritodrine in pregnant women during preterm labour. Am J Obstet Gynecol 1983;147:752-759. 4 Gandar R, de Zoete.n LW, van der Schoot JB. Serum level of ritodrine in man. Eur J Pharmacol 1980;17:117-122. 5 Gladtke E. von Hallingberg HM. Pharmacokinetik, Vol. 13. Berlin: Springer Verlag, 1973. 6 Holleboom CAG. Merkus JMWM. A new infusion scheme for intravenous tocolysis with ritodrine based on the pharmacokinetic aspects of the drug. Eur J Obstet Gynecol Reprod Bioll986;21:121-123. 7 Ingels F, Thieny M, Belpaire F, Bogaert M. Search for rational ritodrine dose regimen in preterm labour. IRCS Med Sci 1985;13:205-206. 8 Keirse MJNC. A survey of tocolytic drug treatment in preterm labour. Br. J Obstet Gynecol 1984;91:424-430. 9 Post LC. Pharmacokinetics of beta-adrenergic agonists. In: Anderson A, et al, eds. Preterm Labour. London: Royal College of Obstetricians and Gynecologists, 1977:134-137. 10 Smit DA, Essed G.G.M, de Haan J. Serum levels of ritodrine during oral maintenance therapy. Gynecol Obstet Invest 1984;18:105-112. 11 Steenhoek A. Drugs given by intravenous infusion. Groningen, 1982. Academic thesis. 12 Thomas K, van Krieken L, van Lierde M. Characterization of ritodrine radio-immune assay. Gynecol Obstet Invest 1982;14:151-155. 13 Wesseliusde Gasparis, et al. Result of double-blind, multicentre study with iitodrine in preterm labour. Br Med J 1971;3:144-147.
Eur. J. Obstet. Gynecol. Reprod Biol., 26 (1987) 119-126 Elsevier
ELJO 00521
A loading-dose infusion scheme for intravenous tocolysis with ritodrine: a pilot study C.A.G. Holleboom
‘, J.M.W.M.
Merkus
’ and L.W.M.
van Elferen
2
’ Department of Obstetrics and Gynecology, Maria Hospital Tilburg, The NetherIan& and 2 Department of Clinical Research Duphar Nederland BV, The Netherlands Accepted for publication 14 May 1987
A loading-dose infusion scheme for intravenous ritodrine therapy was tested in twelve patients with preterm labour. We started with a rather high (386 ~g/min) infusion rate, but the moment tocolysis was reached this infusion rate was reduced to a level needed to maintain the plasma concentration then found. Plasma samples of ritodrine were taken the moment tocolysis was reached and in the steady state, and compared with each other and with expected and calculated plasma concentrations. In the dynamic loading phase we found a half-life for ritodrine of 1 h. This half-life of 1 h can be explained by cumulation of ritodrine in the central compartment and is therefore called cumulation t,,,. In developing an infusion scheme with a loading dose for ritodrine, this cumulation t,,, of 1 h should be taken into account. Cumulation t ,,*;
Ritodrine plasma level
Introduction
Beta-2-sympathomimetics are potent drugs designed to reduce uterine activity. They are used worldwide in preventing preterm labour [l]. Usually the initial therapy is started intravenously [1,8]. All currently applied intravenous dose regimens are empirical, and a rational dosage scheme based on plasma concentrations and related to the pharmacokinetic properties of the beta-mimetic drug has not been developed until now. Correspondence: C.A.G. Holleboom, Department of Obstetrics and Gynecology, Deelenlaan 5, 5042 AD Tilburg, The Netherlands.
0028-2243/87/%03.50
Maria Hospital, Dr
0 1987 Elsevier Science Publishers B.V. (Biomedical Division)
120 TABLE I Ritodrine dosage protocol Initial infusion rate: 386 pg/min tocolysis after
reduce dosage to
o-45 mill 46 min-1 h 15 min lh16rnin-2h 2h-3h 3h-4h 4 h-6 h 6 h-10 h
97 Pgmn 144 ag/min 193 pg/min 241 pg/min 288 pg/min 336 &min 386 &min
Initially a parenteral fixed dose regimen was applied [13], but this has now largely been replaced by an incremental dosage scheme [l]. With this incremental dosage scheme a low initial dose is increased every lo-15 minutes with a fixed dose until uterine contractions stop or unacceptable side-effects develop. In general, at cessation of uterine activity the infusion rate is maintained. However, due to the pharmacokinetic properties of these drugs the plasma concentration will subsequently increase above the level reached at that time, leading to more frequent and serious dose-related side-effects [lo]. To avoid this overdose we tried to develop an infusion scheme starting with a rather high intravenous infusion rate of ritodrine (386 pg/rnin) until contractions disappeared, subsequently reducing the infusion rate to the level needed to maintain the concentration reached at that time. To test the validity of this infusion scheme we compared plasma concentrations found at the moment of tocolysis with plasma concentrations in the steady state. An abstract of this study has been published [6]. Phannacokinetic
background
The rise of the plasma level of a drug, when given by intravenous infusion, is shown in Fig. 1. After the start of the infusion the concentration rises until the steady state is reached. The height of the plasma level depends on the pharmacokinetic properties of the drug, such as its distribution volume (I’,) and its elimination rate constant (K,) as well as the infusion rate (R) and the lapse of time after the start of the infusion (t). The blood concentration C, (mg/ml) can be expressed by means of the following equation [51:
c,=
&D
e (1 - emKer)
The elimination rate constant is related to the drug half-life (ti,z) according to K = 0.693 e h/2
121
Fig. 1. Build-up of the blood level of a drug given by intravenous CS, = steady-state concentration; R = infusion rate.
infusion.
f,,* = half-life
of the drug;
In the steady state, t is large as compared to t,,*, which gives:
In this steady-state situation the concentration of the drug (C,,) is determined by the infusion rate (R) and the clearance (V,K,). The above is valid for drugs with first-order kinetics (the majority) and an open one-compartment model. Fqn. 1 can be turned into: C, = <,,(l - e-o.693.$) If, for instance, the time after the start of the infusion (t) is equal to t1,2 of the infused drug c
, the corresponding
plasma concentration
is:
‘-
From this it can be calculated that after one t,,,, 50% of the final steady state is reached; after two t,,, it is 75%; after three t,, 87.5%, etc. Similarly, the steady-state concentration (about 96.9%) is almost reached after a period of approximately 5-times the half-life of the drug. Should this model be applied to the inhibition of labor with beta-2-sympathomimetics, the desirable infusion rate can be determined from the uterine activity and the duration of the infusion. Patients and procedures Twelve healthy patients in preterm labour, mean gestational age 208 f 30 (SD) days (see Table II), were treated intravenously with ritodrine according to the protocol after giving their informed consent for participation in the study. Adequate plasma samples could not be obtained from three patients. Preterm labor was defined as more than 10 uterine contractions in 30 min before the 36th week of
122 TABLE II Characteristics of the 12 patients (means f S.D.) n Age 01) Weight (kg) Height (cm) Gestational age (days) Range Bishop score Tocolysis index (Baumgarten)
28.6+ 4.3 5&l* 7.6 167 f 8.1 208 f 30 159 f241 3.5* 1.7 2.6$- 1.2
12 11 10 10 11 11
gestation. All patients were healthy and none of them had used beta-mimetics during pregnancy. Besides ritodrine and bed-rest no other treatment had been given. Fifty mg ritodrine (5 ml) were dissolved in 45 ml 5% glucose (1 mg/ml) and administered by an infusion pump (Razel, type A99, flow-rate 1.43-30 pi/h). The infusion was started at a level of 386 pg/min ritodrine and reduced according to the protocol when no contractions were observed for more then 15 min (see protocol). This lower dosage was unchanged for at least 48 h. The infusion scheme is based on the reported elimination half-life (ti& for ritodrine of 2 h [4]. Blood samples were taken both when tocolysis was reached or 2 h after starting the infusion (C,) and in the expected steady state (C,,) (20-24 h after reducing the infusion rate). Ten ml of blood were taken from the cubital vein opposite the infusion arm, heparinized and centrifuged (300 rpm) and the supematant was stored at -20°C until the time of analysis. The ritodrine plasma levels were measured at the Duphar Research Laboratories, Weesp, The Netherlands, by the radioimmunoassay method, previously published by Gandar et al. [4] and Thomas et al. [12]. No information on the infusion rate used was available in the laboratory. The sensitivity of this RIA is 0.1 ng/ml, cross-reaction with ritodrine metabolites 0.2% and coefficient of variations 4.1%. Pharmacokinetic calculations were done with the above-mentioned formulae. Statistical evaluation was performed with Pearson correlation and Wilcoxon matched-pairs signed-ranks tests. A p-value of 0.05 or less is regarded as being statistically significant. Results
All patients tolerated the infusion scheme well and no serious side-effects compelling us to change or stop the infusion rate developed. Changes in maternal and fetal heart rate and blood pressure are given in Table III. A change of more than 5 mmHg in systolic and diastolic blood pressure and 10 mmHg in pulse pressure with pretreatment values was regarded as being a significant difference. In the maintenance period no dose adjustments were necessary because uterine contractions did not recur. Tocolysis was achieved in all 12 patients within 8 h and in 9 out of 12 patients within 1.30 h (Table IV). This means that to maintain tocolysis 9 out of 12 patients required less than 200 pg/min ritodrine.
123 TABLE
III
Pretreatment and maximum values during treatment in the first 6 h of maternal heart rate (MHR), fetal heart rate (FHR), systolic blood pressure, diastolic blood pressure and pulse pressure in relation to time of occurrence after starting the infusion (I,,). Pretreatment (n = 12) MHR (beats/mm) mean f SD range FHR (beats/mm) meanfSD range Systolic BP (mmHg) mean f SD range Pulse pressure (mmHg) mean 5 SD range Diastolic BP (mmHg) mean f SD range Dose adjustment mean * SD range a Significantly b Significantly
During
first 6 h of treatment
max. values
t max Win)
fl9*17 60-116
126+20 80-150
=
52k37 5-120
144*13 120-160
168k15 140-200
a
82+64 15-240
124k 15 105-155
140*14 120-170
=
20b*11 5-30
46*11 30-65
68&12a 50-85 min. values 6Ok9 a 40-75
78k9 60-95
36 bf22 10-90 56+32 15-120 124+151 13-480
different from pretreatment (p < 0.005). before dose adjustment (p < 0.05).
With the measured plasma concentrations in the starting phase (C,) and steady(Table V). This state concentrations (C,,) a t,,, of 50 f 20 min was calculated half-life of 50 f 20 min is not the same as the elimination t,,, of 2 h used in our
TABLE
IV
Time elapse before Patient 1 2 3 4 5 6 7 8 9 10 11 12
No.
tocolysis
and dose adjustments
Tocolysis 13 25 29 33 36 1 hll 1 h36 3h 5 8h 1 h30 45 6 h 20
reached
after (min)
Dosage 97 97 97 97 97 144 193 241 386 193 97 336
to ( pg/min)
124 TABLE
V
Concentration at moment of tocolysis (C,), measured steady-state concentration (C,,), calculated steady-state concentration for tt,s = 2 h (C,,: t1,2= 2 h), calculated steady-state concentration for t t,r = 1 h (C,, : Q = 1 h) and cumulation 1,,, Patient No.
C, (ng/mU
1 2 3 4 5 6 7 8 9 MeanfSD
22 35 100 37 64 47 96 84 a 89 a 64f29
Cumulation q
C,
Calculated CSS:t,,,=l
(ng@)
(ng/nQ
(ng/mU
(mm)
78 66 163 54 86 53 112 105 126 94k36
34 43 50 32 24 34 71 51 98 49&23
40 36 88 30 47 32 71 70 97 57k25
50 74 29 65 23 67 59 21 63 5Ok20
Calculated C,, : 11~2 =
Measured 2 h
h
a Plasma samples taken 2 h after start of the infusion.
dosage scheme. This is probably a result of distribution from central to peripheral compartments and elimination processes. The t,,, reflects the pharmacodynamics of ritodrine in the loading phase of the infusion and is called by us the cumulation t,,,. The cumulation t,,, is the time needed after starting the infusion to reach half of the steady-state concentration without changing the infusion rate. As a result of plasma concentrations in the steady state this discrepancy in t,,, the measured (C,, = 49 f 23 ng/ml) were lower than the calculated C,, for t,,, = 2 h (see Table
140- Css talc RITODRINE
nglml
i 120-
-1-1-1-1 20
40 60 80 100 Css measured nglml
Fig. 2. Correlation between measured and calculated steady-state concentrations
for t1,2 = 1 h.
125
V). Comparison of calculated G, for h/2 = 1 hour with measured C,, revealed a good correlation. Correlation coefficient r = 0.81 (Pearson), significance p < 0.01 (Fig. 2). Discussion
The incremental dosage scheme used for intravenous tocolysis with beta-Zmimetits leads to overdose (Fig. 3). This is inherent in the scheme, because the contractions disappear before the steady-state concentration for that infusion rate is reached. It is better to reduce an initially fixed infusion rate to a dose level needed to maintain the effective concentration reached at that moment [7,10,11]. Ingels et al. [7] found steady-state concentrations of ritodrine after 2 h of infusion instead of the expected 6-8 h; Post [9] also observed this phenomenon. This is a consequence of cumulation of ritodrine in the central compartment. We studied an infusion scheme for ritodrine based on the reported half-life of 2 h [4]. Evaluating the results the cumulation t,,, was 50 f 20 min rather than the . . . reported elumnation t,,, of 2 h. This explains the difference in calculated and measured steady-state concentrations and in effective and measured steady-state concentrations. We observed interindividual differences in cumulation t,,, (21-74 min) which could have been due to individual differences in metabolism. The influence of pregnancy on ritodrine metabolism is not completely clear. Changes in liver metabolism, renal clearance, compartment and volume enlargement all play a role [2]. The infusion scheme used in our study takes these inter-individual differences into account: the infusion rate is reduced after contractions have disappeared and not after a fixed time. The degree to which the infusion rate is reduced is based on the pharmacokinetic considerations mentioned above. Further studies are needed in order to conclude whether reduction of the infusion rate with a scheme based on accumulation I,,~ = 1 h is feasible. Besides the lower risk of an excessively high plasma concentration, another advantage of the infusion scheme studied is that fewer dose adjustments are
n.
css
.
c:T______ !
plasma
level
needed
for tocdysis
Fig. 3. Overdose given after tocolysis is achieved at time A. C, = plasma concentration with infusion rate R. C,, = steady-state concentration reached with infusion rate R.
reached
at time A
126
necessary (only to reduce the infusion rate at time of tocolysis), which also leads to fewer side-effects. Side-effects depend not only on the absolute concentration of ritodrine; the rate of change in the infusion rate or drug concentration may be more important [3]. Finally, by using a high loading dose, effective plasma concentrations are achieved more rapidly than with the incremental dosage scheme, so the intended effect (tocolysis) can be expected earlier. Conclusions The proposed dosage scheme for intravenous ritodrine is in practice well-accepted by patients and needs very few dose adjustments. Instead of the reported elimination r,,, of 2 h a cumulation t,,z of 1 h should be used in developing a loading dose infusion scheme. This infusion scheme makes it possible to reach and maintain the minimal effective dosage in the individual patient. A new study with an infusion scheme based on the cumulation t,,, of 1 h is in progress. Acknowledgements We wish to thank L.W. de Zoete of the Duphar Company, Weesp, The Netherlands, for the determination of the ritodrine plasma concentrations by the RIA methodology. References 1 Barden TP, Peter JB, Merkatz IR. Ritodrine hydrochloride: A beta-mimetic agent for use in preterm labor. Obstet Gynecol 1980;56:1-6. 2 Bogaert MC, Thiery M. Phannacokinetics and pregnancy. Eur J Obstet Gynecol Reprod Biol 1983;16:229-235. 3 Caritis SW, Lin LS, Wong LK Pharmacodynamics of ritodrine in pregnant women during preterm labour. Am J Obstet Gynecol 1983;147:752-759. 4 Gandar R, de Zoete.n LW, van der Schoot JB. Serum level of ritodrine in man. Eur J Pharmacol 1980;17:117-122. 5 Gladtke E. von Hallingberg HM. Pharmacokinetik, Vol. 13. Berlin: Springer Verlag, 1973. 6 Holleboom CAG. Merkus JMWM. A new infusion scheme for intravenous tocolysis with ritodrine based on the pharmacokinetic aspects of the drug. Eur J Obstet Gynecol Reprod Bioll986;21:121-123. 7 Ingels F, Thieny M, Belpaire F, Bogaert M. Search for rational ritodrine dose regimen in preterm labour. IRCS Med Sci 1985;13:205-206. 8 Keirse MJNC. A survey of tocolytic drug treatment in preterm labour. Br. J Obstet Gynecol 1984;91:424-430. 9 Post LC. Pharmacokinetics of beta-adrenergic agonists. In: Anderson A, et al, eds. Preterm Labour. London: Royal College of Obstetricians and Gynecologists, 1977:134-137. 10 Smit DA, Essed G.G.M, de Haan J. Serum levels of ritodrine during oral maintenance therapy. Gynecol Obstet Invest 1984;18:105-112. 11 Steenhoek A. Drugs given by intravenous infusion. Groningen, 1982. Academic thesis. 12 Thomas K, van Krieken L, van Lierde M. Characterization of ritodrine radio-immune assay. Gynecol Obstet Invest 1982;14:151-155. 13 Wesseliusde Gasparis, et al. Result of double-blind, multicentre study with iitodrine in preterm labour. Br Med J 1971;3:144-147.