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PHARMACOKINETICS

Effect of Drospirenone on Serum Potassium and Drospirenone Pharmacokinetics in Women With Normal or Impaired Renal Function

Rolf Schürmann, MD, Hartmut Blode, PhD, Norbert Benda, PhD, Maureen Cronin, MD and Andreas Küfner, MD

From Corporate Clinical Development G+A, Schering AG Berlin (Dr Schürmann); Clinical Pharmacokinetics, Metabolism, Bioanalytics, Schering AG Berlin (Dr Blode); Biometry G+A, Schering AG Berlin (Dr Benda); Coordination G+A, Schering AG Berlin (Dr Cronin); and COE Data Management, Schering AG Berlin (Dr Küfner).


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
This open-label study investigated whether drospirenone, a novel progestin with antimineralocorticoid properties, increases the risk for hyperkalemia in subjects with renal impairment. Women with normal renal function and mild or moderate renal impairment were given drospirenone 3 mg/d for 14 days. Mean serum potassium concentrations did not significantly change during steady-state drospirenone treatment. No difference in drospirenone effects on serum potassium concentrations in subjects with renal insufficiency versus subjects with normal renal function was found. Steady-state pharmacokinetics was similar in subjects with normal renal function and mild renal impairment, whereas, due to results from 1 subject, drospirenone exposure was slightly higher in the moderate renal impairment group. Given the reported tolerability of drospirenone, this small increase in serum drospirenone is not expected to be clinically significant. In conclusion, this study demonstrated that drospirenone has no significant effect on serum potassium levels in patients with mild to moderate renal insufficiency.

Key Words: Drospirenone • renal function • hyperkalemia • progestin • pharmacokinetics

Drospirenone (DRSP) is a novel synthetic progestin with antimineralocorticoid and antiandrogenic properties, which makes it similar to natural progesterone.1-4 Drospirenone is almost completely metabolized: less than 1% of the administered dose is excreted in the urine as unchanged drug.5,6 The metabolites of DRSP undergo both hepatic and renal elimination. Based on receptor-binding studies, the metabolites excreted in urine are devoid of pharmacologic activity.6 DRSP's antimineralocorticoid properties are typified by a small increase in sodium excretion and thus a slight loss in body weight.1 However, potassium excretion remains unaffected. When DRSP is combined with ethinyl estradiol for contraception7,8 or with estradiol for hormone replacement therapy, these mild antimineralocorticoid activities offer further clinical advantages, such as avoiding fluid retention and weight gain.

Other antimineralocorticoid medications, such as spironolactone, can cause hyperkalemia in patients with chronic renal failure due to their limited potassium excretory capacity.9 In subjects with normal renal function, the risk for hyperkalemia is generally negligible during such therapy. Other drugs, including angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), trimethoprim, and potassium-sparing diuretics can also promote hyperkalemia in subjects with renal impairment or other underlying disease states in which potassium excretion is compromised.10-12 In clinical trials, DRSP either alone or in combination with an estrogen was not observed to promote potassium retention,1,13 but its effect in patients with renal impairment has not yet been evaluated.

The primary aim of this study was to assess the effect of steady-state treatment with DRSP on serum potassium concentrations in females with mild to moderate renal impairment to ascertain if they are at increased risk for hyperkalemia. Drospirenone serum levels were also evaluated as a secondary target variable to assess the effect of renal function on the steady-state pharmacokinetics of DRSP.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
Healthy females aged 18 to 75 years were eligible for study participation if they had creatinine clearance (CLCR) = 30 mL/min and a body mass index of 18 to 29 kg/m2. For screening, CLCR was estimated from serum creatinine concentrations using the Cockcroft-Gault formula.14 Health status was documented from a general and gynecologic medical history and examination, measurement of vital signs and electrocardiograms, and clinical laboratory testing. Fertile subjects were required to have spontaneous menstrual cycles of 24 to 35 days and had to agree to use nonhormonal methods of contraception (barrier method or intrauterine device) during the study or to be abstinent. Previously pregnant subjects were eligible if 6 months had elapsed following childbirth, abortion, or lactation. All subjects were required to provide signed informed consent before receiving the study drug.

Subjects were excluded if they had clinically relevant gynecologic findings; a history, suspicion, or previous diagnosis of cancer; benign liver or pituitary tumors; thromboembolic disease or conditions increasing susceptibility to these diseases; type 1 diabetes; severe dyslipidemia; migraine accompagnée; a history of drug or alcohol abuse; or any condition within 4 weeks before the study that could affect serum potassium levels. A serum potassium concentration > 4.8 mmol/L, positive pregnancy or drug test, current or recent smoking, recent blood donation, use of special diets, and extreme physical exertion within 1 week of the study also resulted in study exclusion. Sex hormones, including contraceptives, were not allowed within 6 weeks (or within 6 months for long-acting preparations) before study drug administration. Systemic or topical medications that could affect serum potassium levels or drug metabolism enzymes were not allowed within 8 weeks before the first dose of study drug. However, because most patients with renal insufficiency use antihypertensive treatment, intake of ACE inhibitors, angiotensin II receptor antagonists, or ß-blockers was allowed. As these medications do not lower but potentially increase potassium concentrations, their use would not have counteracted but could have potentially amplified the putative hyperkalemic antimineralocorticoid effect of DRSP. As can be seen in Table I, a total of 7 (25%) of the 28 subjects continued to use antihypertensive medication that had the potential to elevate their potassium concentration during the study.


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  		Table I Intake of Comedication With Potential to Affect Potassium Levels

 

Study Design
This open-label, nonrandomized, single-center study was conducted by ITEC Pharmacology in Paris, France, in accordance with the ethical principles of the Declaration of Helsinki and its amendments and the guidelines of Good Clinical Practice. The study protocol was approved by 2 independent ethics committees (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale, Centre Hospitalier de Saint-Germain-en-Laye, Saint-Germain-en-Laye, France, and Bayrische Ärztekammer, Ethik-Kommission, München, Germany).

Subjects were divided into 3 groups according to renal function based on their 24-hour urinary CLCR at baseline. The 3 groups were defined as normal renal function (CLCR > 80 mL/min; group 1), mild renal impairment (CLCR > 50 to 80 mL/min; group 2), and moderate renal impairment (CLCR 30 to 50 mL/min; group 3). All subjects received 1 tablet of DRSP 3 mg daily for 14 days. Subjects took the study drug at the same time each day (1900–2100). Dosing in subjects with a menstrual cycle started on day 15 of their individual cycle and continued until day 28. Subjects who were no longer menstruating started DRSP at any time after inclusion. Subjects were allowed to eat and drink as usual but fasted in the morning of the days when blood samples were collected. Based on a request of 1 ethics committee, subjects were provided with a list of foods with high potassium content and instructed to avoid their intake to reduce possible influences of external diet on the study's primary target variable.

Assessments
Blood samples for analysis of serum potassium levels were collected on 3 consecutive days at both baseline and during steady-state treatment with DRSP. At baseline, blood was collected on the 2 days before treatment and immediately before the first dose of DRSP on day 1. At steady state, blood was collected 12 hours after DRSP administration on days 13 and 14 and also on the day following the last dose. Serum potassium concentrations at baseline and at steady state were calculated as the arithmetic mean of the 3 consecutive measurements.

Blood samples for DRSP pharmacokinetics were collected the day before treatment (pretreatment) and immediately before dosing (trough level), as well as 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours after dosing on day 14.

The safety analysis also included measurement of serum potassium levels every second day throughout the study. In addition, the safety assessment included monitoring for adverse events as well as assessment of clinical laboratory parameters before treatment and at the end of the study.

Serum Potassium Levels
Serum potassium was measured using an ion-selective electrode. This electrode contained a potassium-selective valinomycin membrane. The diffusion of the potassium ions created a positive charge that was measured against a reference electrode. The selectivity of the membrane was 1000 ions of potassium against 1 ion of sodium. The procedure was insensitive to H+ ions for a pH value between 3 and 9.

All patient data were included in both the efficacy and safety potassium analyses (n = 28). The relationship between renal function and changes in serum potassium concentration was analyzed by multiple linear regression of the log-transformed potassium values during treatment with DRSP (mean of days 13, 14, and 15) using the factors age, CLCR, log-transformed pretreatment potassium values, and interaction between CLCR and log-transformed pretreatment potassium values.

Pharmacokinetics
Serum DRSP concentrations were determined using a specific, validated radioimmunoassay as described previously.15 Based on quality control samples analyzed at 3 concentration levels together with the study samples, the method's interassay precision was between 5.8% and 9.5%, and its accuracy was between 101% and 106%.

Protein binding of DRSP was determined by equilibrium dialysis using weighted serum pools. These were prepared for individual subjects from the samples collected within 24 hours after the last drug dose based on the trapezoidal rule.16 [3H]-DRSP (70 000 cpm) was added to each pool sample, and then triplicate 250-µL serum aliquots were dialyzed against 250 µL of dialysis buffer for 3 hours at 37°C. The unbound fraction (fu) was calculated according to the method of Hu and Curry.17

For the pharmacokinetic parameters, the geometric mean and geometric coefficient of variation were calculated. The maximum serum concentration (Cmax) of DRSP and the time to reach this level (tmax) were determined directly from the measured serum levels. For tmax, the median and range were calculated. The dependency of area under the serum concentration versus time curve at steady state within a dosage interval (AUC0-24) on renal function was analyzed by a linear regression analysis of the log-transformed AUC0-24 for DRSP. The terminal rate constant ({lambda}z) of the disposition of DRSP in serum was calculated by regression analysis of the linear part of a semilogarithmic plot of serum concentration versus time. The corresponding terminal half-life (t1/2) was calculated as ln2/{lambda}z. The AUC0-24 was calculated by the trapezoidal rule using measured serum concentrations from last dosing (day 14) until 24 hours thereafter. The total oral clearance of DRSP at steady state (CLss/F) was calculated from the ratio of drug dose on day 14 to AUC0-24.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Disposition and Demographics of Subjects
Of the 38 subjects screened for this study, 28 subjects were enrolled and all completed the study. Women were excluded from the study due to abnormal medical examination findings (n = 2), withdrawal of consent (n = 2), absence of gynecologic examination (n = 1), intake of excluded comedication (n = 1), and for nonmedical reasons (n = 4). Of the 28 women included, 11 (39%) women had normal renal function at baseline, 10 (36%) subjects had mild renal impairment, and the remaining 7 (25%) women had moderate renal impairment. Demographic characteristics of the subjects in each group were similar (Table II). All women were white, and most (61%) were premenopausal. Although the mean age of subjects with renal impairment was higher than those with normal renal function, the age range of the 3 groups was similar.


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  		Table II Subject Demographics

 

Serum Potassium Concentrations
The primary variable in this study was the change in serum potassium concentration from before to during steady-state treatment with DRSP. As expected, individual and mean serum potassium levels at baseline were higher in subjects with renal impairment than in those with normal renal function (Figure 1; Table III). All individual baseline serum potassium measurements were less than 5.3 mmol/L, except for 1 subject with 1 measurement of 5.7 mmol/L on day 1 before DRSP dosing. Because all the other pretreatment values for this subject were less than 4.8 mmol/L, it appears likely that the high value was due to mishandling (eg, venous stasis or mild hemolysis) of the sample during sampling or during the storage process. The subject was allowed to continue participation.


Figure 1
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  		Figure 1. Mean potassium concentrations (± SD) for different groups during the entire study.

 

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  		Table III Mean ± SD Serum Potassium Concentrations (mmol/L)

 

At DRSP steady state, all individual serum potassium measurements were less than 5.5 mmol/L for all subjects in each of the 3 groups. As expected, the mean serum potassium levels at DRSP steady state remained higher in subjects with renal impairment than in those with normal renal function (Table III). None of the subjects showed an appreciable change in serum potassium levels at steady state compared with pretreatment values (Figure 1). The mean difference in serum potassium levels between DRSP steady state and baseline was negligible in each group: –0.1 mmol/L for subjects with normal renal function as well as with moderate renal impairment and –0.2 mmol/L in those with mild renal impairment. The maximum change for any individual in the pretreatment to treatment mean concentrations was 0.33 mmol/L. Thus, the mean serum potassium concentrations did not change appreciably during steady-state treatment with DRSP in any of the renal function groups (Figure 2).


Figure 2
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  		Figure 2. Mean serum drug concentrations versus time after 14 daily doses of drospirenone (DRSP) 3 mg in women with normal renal function (closed circles), mild renal impairment (open squares), and moderate renal impairment (closed triangles).

 

Additional serum potassium levels were measured every other day during DRSP treatment as part of the safety analysis. All but 1 potassium measurement during treatment were below the level of 5.5 mmol/L. One subject in group 3 had a serum potassium level of 5.5 mmol/L on day 9 of treatment. None of this subject's subsequent potassium levels during DRSP treatment were higher than 5.2 mmol/L.

Modeling of Serum Potassium Data
A multiple regression model was used to predict changes in serum potassium concentration during treatment with DRSP (r2 = .702). Pretreatment serum potassium levels (P = .004) had a significant effect on DRSP steady-state serum potassium concentration. Age (P = .599), CLCR (P = .174), and the interaction between CLCR and baseline serum potassium (P = .146) were not statistically significant, and their estimated effects were negligible.

Serum Creatinine and Serum Sodium Levels
Serum creatinine and serum sodium levels were also measured at baseline and at steady-state treatment with DRSP. At baseline, serum creatinine reflected the level of renal function, with mean levels of 0.78 mg/dL in the group with normal renal function and 1.09 mg/dL and 1.73 mg/dL in the groups with mild and moderate renal impairment, respectively. The mean serum creatinine levels did not change during DRSP treatment. Baseline serum sodium levels in all 3 groups were within the normal range (135–148 mmol/L). During DRSP treatment, the change in mean serum sodium levels reflected an antiminer-alocorticoid effect, which was greater in the renally impaired groups (–1.5 mmol/L in the normal renal function group, –5.1 mmol/L in the mildly impaired group, and –8.6 mmol/L in the moderately impaired group). Nevertheless, the mean sodium levels remained within the normal range for the groups with normal renal function (138.0 mmol/L) and mild renal impairment (138.7 mmol/L) and just below the normal range for the group with moderate renal impairment (133.3 mmol/L). Two subjects with moderate renal impairment had serum sodium levels below 130 mmol/dL at DRSP steady state; both had had low-normal levels at baseline.

DRSP Pharmacokinetics
Mean serum concentrations of DRSP in subjects with normal renal function and mild renal impairment were nearly superimposable, whereas subjects with moderate renal impairment had somewhat higher mean serum DRSP concentrations (Figure 3). In subjects with normal renal function, the geometric mean of Cmax was 35.8 ng/mL. The maximum concentration was reached about 4 hours (median) after administration (Table IV). The geometric mean Cmax values were 11% and 18% higher in subjects with mild and moderate renal impairment, respectively, whereas tmax was similar among the 3 groups. The steady-state exposure of DRSP (AUC0-24) was similar in subjects with normal renal function and mild renal impairment, but the mean was increased by 37% in the moderate renal impairment group. The higher serum drug concentrations in subjects with moderate impairment were associated with a mean oral clearance of DRSP that was 27% lower than the mean in the normal renal function group. Binding of DRSP to serum proteins was similar in the 3 groups: the mean ± SD free fraction (fu) of DRSP in serum was 4.2% ± 0.2%, 5.4% ± 1.5%, and 3.7% ± 0.8% in the normal renal function, mild impairment, and moderate impairment groups, respectively.


Figure 3
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  		Figure 3. Relationship between AUC0-24 of DRSP at steady state and CLCR. The regression line obtained on log-scale was retransformed to original scale. The slope was statistically significant (P = .028, r = .41). DRSP, drospirenone; CLCR, creatinine clearance.

 

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  		Table IV Pharmacokinetics of Drospirenone (DRSP) at Steady State

 


Figure 4
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  		Figure 4. Change in potassium: baseline to end of treatment (days 13-15).

 

Taking all subjects and their individual baseline CLCR into consideration, a trend to increasing serum DRSP exposure with decreasing CLCR was observed (Figure 4). This trend was substantially influenced by 1 subject with moderate renal impairment, who had an approximately 2-fold higher AUC0-24 value than the group mean. Nevertheless, there was no indication that protein binding or comedication intake biased the pharmacokinetics of this subject. Based on a linear regression analysis of log-transformed AUC0-24 values in relation to CLCR, a statistically significant increase in DRSP exposure with decreasing CLCR was observed (P = .028, r = .41). According to this relationship, exposure to DRSP would be expected to increase by 3.5% (95% confidence interval: 0.4% to 6.9%) with a reduction in CLCR of 10 mL/min.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
This study demonstrates that serum potassium concentrations were not altered in a statistically significant or clinically meaningful manner during steady-state treatment with 3 mg DRSP in subjects with normal renal function as well as in those with mild to moderate renal impairment. These results are clinically important because past studies have demonstrated that this DRSP dose is sufficiently pharmacologically active to effectively suppress ovulation in normal healthy women and is the dose that is used in the standard oral contraceptive preparation.8 Past studies have also demonstrated that steady-state pharmacokinetics is reached with 3 mg DRSP within the 14-day treatment period investigated in this study.6

At baseline as well as during steady-state DRSP treatment, serum potassium concentrations were somewhat higher in subjects with renal impairment than in those with normal renal function. This finding was expected and was caused by the reduction in renal potassium excretory capacity that accompanies renal insufficiency. In all 3 renal function groups, mean potassium concentrations were slightly lower during steady-state DRSP treatment than at baseline. Moreover, individual serum potassium levels at DRSP steady state for all 28 subjects included in this study were well below levels that could pose a risk of clinical hyperkalemia (≥5.5 mmol/L). It is possible that the small total number of subjects in this phase I study may have influenced these findings. However, comparable results have recently been reported in a larger population of patients at high risk for hyperkalemia.18 In that study, treatment with a combination of 3 mg DRSP and 1 mg 17ß-estradiol was not associated with a greater incidence of hyperkalemia than placebo treatment in patients with and without type 2 diabetes mellitus and concomitant use of ACE inhibitors, angiotensin receptor antagonists, or ibuprofen.18 Thus, based on these study results, the putative risk for hyperkalemia induced by DRSP does not appear to have clinical relevance in patients with mild or moderate renal impairment.

Sodium intake was not monitored in this outpatient setting and thus may constitute a potential limitation of the study. However, high intake of sodium that could have an effect on potassium levels appears unlikely, particularly in those subjects treated for hypertension.

Patients with renal impairment often take potassium-sparing medications. Although none of the subjects who combined DRSP with these medications developed hyperkalemia in this study, concomitant use of more than 1 potassium-sparing drug could lead to an increase in potassium levels above the normal range, particularly if levels are in the high-normal range before treatment.

In addition, DRSP did not affect mean serum creatinine levels in this study, suggesting that the drug did not have an adverse impact on renal function in subjects with renal insufficiency. Finally, DRSP resulted in a decrease in serum sodium concentrations, which was somewhat more pronounced in the renally impaired groups. This change in serum sodium reflects the mild antimineralocorticoid property of DRSP and is consistent with the increased rate of sodium excretion seen in previous clinical trials with DRSP in healthy women.1,13

This study also demonstrates that the steady-state DRSP pharmacokinetics is similar in women with normal renal function and mild renal impairment. This was also true for the majority of women with moderate renal impairment. However, because of 1 subject, whose AUC0-24 was approximately 2-fold higher than the mean for the group, mean exposure to DRSP at steady state (AUC0-24) was, on average, 37% higher in this group as compared to the group with normal renal function. Thus, a statistically significant increase of the DRSP AUC0-24 with decreasing CLCR was observed in a linear regression analysis in this study. After exclusion of this subject from the regression analysis, the correlation between AUC0-24 values and CLCR was no longer statistically significant.

In addition, this subject's remaining laboratory testing and general tolerability of the drug did not differ from others in the moderate renal impairment group. Moreover, this individual's AUC0-24 cannot be considered unexpectedly high; similar values have been occasionally observed in healthy young subjects taking the same DRSP dose in other pharmacokinetic studies.15 Similar kinetic variability is also observed with other progestins. Considering the excellent tolerability of DRSP, even a moderate increase in serum DRSP levels would not be expected to be of clinical relevance.

In summary, this study demonstrated that DRSP pharmacokinetics remained virtually unchanged in subjects with mild renal impairment. A trend toward increasing exposure to DRSP can be expected in subjects with moderate renal impairment. However, this slightly higher exposure is not expected to be of clinical significance. Administration of DRSP to women with mild to moderate renal impairment does not relevantly affect serum potassium levels.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
The excellent technical assistance from Gabriele Al-Yacoub and Claudia Jörg is gratefully acknowledged.

Sponsor: Schering AG. The authors are all employees of Schering AG.

DOI: 10.1177/0091270006289973


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Oelkers W, Berger V, Bolik A, et al. Dihydrospirorenone, a new progestogen with antimineralocorticoid activity: effects on ovulation, electrolyte excretion, and the renin-aldosterone system in normal women. J Clin Endocrinol Metab. 1991;73: 837-942.[Abstract/Free Full Text]

2. Pollow K, Juchem M, Elger W, Jacobi N, Hoffmann G, Mobus V. Dihydrospirorenone (ZK30595): a novel synthetic progestogen–characterization of binding to different receptor proteins. Contraception. 1992;46: 561-574.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. Muhn P, Krattenmacher R, Beier S, Elger W, Schillinger E. Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity. Pharmacologic characterization in animal models. Contraception. 1995;51: 99-110.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

4. Muhn P, Fuhrmann U, Fritzemeier KH, Krattenmacher R, Schillinger E. Drospirenone: a novel progestogen with antiminer-alocorticoid and antiandrogenic activity. Ann NY Acad Sci. 1995;761: 311-335.[Web of Science][Medline] [Order article via Infotrieve]

5. Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception. 2000;62: 29-38.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

6. Blode H. Pharmacokinetics of drospirenone. Gynaecology Forum. 2002;7: 18-23.

7. Parsey KS, Pong A. An open-label, multicenter study to evaluate Yasmin, a low-dose combination oral contraceptive containing drospirenone, a new progestogen. Contraception. 2000;61: 105-111.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

8. Huber J, Foidart JM, Wuttke W, et al. Efficacy and tolerability of a monophasic oral contraceptive containing ethinylestradiol and drospirenone. Eur J Contracept Reprod Health Care. 2000;5: 25-34.[CrossRef][Medline] [Order article via Infotrieve]

9. Waeber B, Nussberger J, Brunner HR. Clinical applications of antimineralocorticoids. J Steroid Biochem. 1988;31: 739-744.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

10. Rimmer JM, Horn JF, Gennari FJ. Hyperkalemia as a complication of drug therapy. Arch Intern Med. 1987;147: 867-869.[Abstract/Free Full Text]

11. Perazella MA. Trimethoprim-induced hyperkalemia: clinical data, mechanism, prevention and management. Drug Saf. 2000;22: 227-236.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

12. Greenberg A. Hyperkalemia: treatment options. Semin Nephrol. 1998;18: 46-57.[Web of Science][Medline] [Order article via Infotrieve]

13. Oelkers W, Foidart JM, Dombrovicz N, Welter A, Heithecker R. Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. J Clin Endocrinol Metab. 1995;80: 1816-1821.[Abstract]

14. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16: 31-41.[Web of Science][Medline] [Order article via Infotrieve]

15. Blode H, Wuttke W, Loock W, Röll G, Heithecker R. A 1–year pharmacokinetic investigation of a novel oral contraceptive containing drospirenone in healthy female volunteers. Eur J Contracept Reprod Health Care. 2001: 256-264.

16. Louton T, Kuhnz W, Dibbelt L, Knuppen R. Weighted serum pools in comparison to the trapezoidal rule for estimating AUCs for ethinyl estradiol: the relationship of the variance of the determination to the interindividual variance. Eur J Clin Pharmacol. 1994;46: 77-81.[Web of Science][Medline] [Order article via Infotrieve]

17. Hu OY, Curry SH. Calculation of fraction bound in equilibrium dialysis with special reference to drug losses by decomposition and absorption. Biopharm Drug Dispos. 1986;7: 211-214.[Web of Science][Medline] [Order article via Infotrieve]

18. Preston RA, White WB, Pitt B, Bakris G, Norris PM, Hanes V. Effects of drospirenone/17-ß estradiol on blood pressure and potassium balance in hypertensive postmenopausal women. Am J Hypertens. 2005;18: 797-804.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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Coadministration of Estradiol/Drospirenone and Indomethacin Does Not Cause Hyperkalemia in Healthy Postmenopausal Women: A Randomized Open-Label Crossover Study
J. Clin. Pharmacol., June 1, 2007; 47(6): 774 - 781.
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