Absence of tolerance and toxicity to high-dose continuous intravenous furosemide in haemodynamically unstable infants after cardiac surgery

What is already known about this subject

• Continous i.v. infusion of furosemide is superior to intermittent administrations, especially in haemodynamically unstable infants, because it results in a more controlled diuresis (although doses are generally chosen rather low).

What this study adds

• High-dose continuous furosemide infusion is an effective treatment for volume overload in haemodynamically unstable infants.
• Development of tolerance to furosemide was not observed despite high doses and prolonged exposure.
• Maximum serum furosemide concentrations remained well below the presumed toxic concentration.

Aim

To evaluate a high-dose continuous furosemide regimen in infants after cardiac surgery.

Methods

Fifteen haemodynamically unstable infants with volume overload admitted to a paediatric intensive care unit were treated with an aggressive furosemide regimen consisting of a loading bolus (1–2 mg kg⁻¹) followed by a continuous infusion at 0.2 mg kg⁻¹ h⁻¹ which was adjusted according to a target urine output of 4 ml kg⁻¹ h⁻¹. Frequent sampling for furosemide concentrations in blood and urine was done for 3 days with simultaneous assessment of sodium excretion and urine output.

Results

The mean furosemide dose was 0.22 (± 0.06), 0.25 (± 0.10) and 0.22 (± 0.11) mg kg⁻¹ h⁻¹ on the first, second and third day, respectively. Median urine production was 3.0 (0.6–5.3), 4.2 (1.7–6.6) and 3.9 (2.0–8.5) ml kg⁻¹ h⁻¹, respectively, on the first, second and third day of the study. The target urine production was reached at a median time of 24 (6–60) h and this was maintained during the study period. The regimen did not result in toxic serum concentrations and was haemodynamically well tolerated.

Conclusion

High-dose continuous furosemide infusion for 72 h in haemodynamically unstable infants after cardiac surgery appears to be a safe and effective treatment for volume overload. Development of tolerance against the effects of furosemide and ototoxic furosemide concentrations were not observed.     

Novel Δ(9) -tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects

AIMS

Among the main disadvantages of currently available Δ⁹-tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®.

METHODS

This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed.

RESULTS

Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t_1/2 was 72–80 min, t_max was 39–56 min and C_max 2.92–4.69 ng ml⁻¹. THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (−2.7 mm, 95% CI −4.5, −0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min^–1, 95% CI 2.7, 6.5). Namisol® was well tolerated.

CONCLUSIONS

Oral Namisol® showed promising PK and PD characteristics. Variability and t_max of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations.     

Pharmacokinetics of intravenous and oral midazolam in plasma and saliva in humans: usefulness of saliva as matrix for CYP3A phenotyping

AIMS

To compare midazolam kinetics between plasma and saliva and to find out whether saliva is suitable for CYP3A phenotyping.

METHODS

This was a two way cross-over study in eight subjects treated with 2 mg midazolam IV or 7.5 mg orally under basal conditions and after CYP3A induction with rifampicin.

RESULTS

Under basal conditions and IV administration, midazolam and 1′-hydroxymidazolam (plasma, saliva), 4-hydroxymidazolam and 1′-hydroxymidazolam-glucuronide (plasma) were detectable. After rifampicin, the AUC of midazolam [mean differences plasma 53.7 (95% CI 4.6, 102.9) and saliva 0.83 (95% CI 0.52, 1.14) ng ml⁻¹ h] and 1′-hydroxymidazolam [mean difference plasma 11.8 (95% CI 7.9, 15.7) ng ml⁻¹ h] had decreased significantly. There was a significant correlation between the midazolam concentrations in plasma and saliva (basal conditions: r = 0.864, P < 0.0001; after rifampicin: r = 0.842, P < 0.0001). After oral administration and basal conditions, midazolam, 1′-hydroxymidazolam and 4-hydroxymidazolam were detectable in plasma and saliva. After treatment with rifampicin, the AUC of midazolam [mean difference plasma 104.5 (95% CI 74.1, 134.9) ng ml⁻¹ h] and 1′-hydroxymidazolam [mean differences plasma 51.9 (95% CI 34.8, 69.1) and saliva 2.3 (95% CI 1.9, 2.7) ng ml⁻¹ h] had decreased significantly. The parameters separating best between basal conditions and post-rifampicin were: (1′-hydroxymidazolam + 1′-hydroxymidazolam-glucuronide)/midazolam at 20–30 min (plasma) and the AUC of midazolam (saliva) after IV, and the AUC of midazolam (plasma) and of 1′-hydroxymidazolam (plasma and saliva) after oral administration.

CONCLUSIONS

Saliva appears to be a suitable matrix for non-invasive CYP3A phenotyping using midazolam as a probe drug, but sensitive analytical methods are required.

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT

• Midazolam is a frequently used probe drug for CYP3A phenotyping in plasma. Midazolam and its hydroxy-metabolites can be detected in saliva.

WHAT THIS STUDY ADDS

• The concentrations of midazolam and its hydroxy-metabolites are much lower in saliva than in plasma, but the midazolam concentrations in both matrices show a significant linear correlation.
• Saliva appears to be a suitable matrix for CYP3A phenotyping with midazolam, but very sensitive methods are required due to the low concentrations of midazolam and its hydroxy-metabolites.

     

Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipients

AIM

To examine inter- and intrapatient variability in the pharmacokinetics of intravenous (i.v.) busulphan given as a single daily dose to children with malignant (n = 19) and nonmalignant (n = 21) disease.

METHODS

Busulphan (120 mg m⁻², 130 mg m⁻² or 3.2 mg kg⁻¹) was administered over median 2.1 h. Blood samples (4–10) were collected after the first dose, busulphan concentrations were measured and pharmacokinetic parameters, including clearance (CL) and area under the concentration–time curve (AUC), were determined using the Kinetica software (Innaphase). Interpatient variability was assessed as percent coefficient of variation (% CV). Intrapatient variability was assessed by calculating percent differences between observed full dose AUC and AUC predicted from an initial 65 mg m⁻² dose in 13 children who had busulphan pharmacokinetic monitoring.

RESULTS

Clearance of i.v. busulphan in 40 children was 4.78 ± 2.93 l h⁻¹ (% CV 61%), 0.23 ± 0.08 l h⁻¹ kg⁻¹ (% CV 35%) and 5.79 ± 1.59 l h⁻¹ m⁻² (% CV 27%). Age correlated significantly (p < 0.001) with CL (l h⁻¹) and CL (l h⁻¹ kg⁻¹), but not with CL (l h⁻¹ m⁻²). AUC normalized to the 130 mg m⁻² dose ranged from 14.1 to 56.3 mg l⁻¹.h (% CV 37%) and also did not correlate with age. Interpatient variability in CL (l h⁻¹ m⁻²) was highest in six children with immune deficiencies (60%) and lowest in seven children with solid tumours (14%). Intrapatient variability was <13% for nine (of 13) children, but between 20 and 44% for four children.

CONCLUSIONS

There is considerable inter- and intrapatient variability in i.v. busulphan CL (l h⁻¹ m⁻²) and exposure that is unrelated to age, especially in children with immune deficiencies. These results suggest that monitoring of i.v. busulphan pharmacokinetics is required.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The pharmacokinetics of oral busulphan given four times daily has been extensively studied.
• Large inter- and intravariability in oral busulphan exposure has led to attempts at pharmacokinetic monitoring.
• However, there have been limitations in the pharmacokinetic analysis due to inadequate characterization of the elimination phase in a 6-h dosing interval, due to late absorption in some patients.
• Intravenous (i.v.) busulphan is a relatively new administration method and there have been relatively few studies on the pharmacokinetics of i.v. busulphan, especially when given as a single daily dose.

WHAT THIS STUDY ADDS

• Inter- and intrapatient variability in i.v. busulphan pharmacokinetics is comparable to that previously observed with oral busulphan, suggesting that pharmacokinetic monitoring is advisable.
• Children with immune deficiencies, in particular, have widely variable exposure.

     

The pharmacokinetic profile of sitaxsentan, a selective endothelin receptor antagonist, in varying degrees of renal impairment

What is already known about this subject

• The initial indication for endothelin (ET) receptor antagonism as a treatment strategy, primary pulmonary hypertension, is now expanding to include scleroderma, which can cause both pulmonary and renal disease.
• It is important to understand the effects of impaired renal function on the pharmacokinetics of these drugs to allow appropriate dosing in individuals with impaired renal function.

What this study adds

• Sitaxsentan, an oral selective endothelin A receptor antagonist, is licensed for the treatment of pulmonary hypertension, and studies of this drug in CKD are planned.
• The pharmacokinetic profile of sitaxsentan is unchanged in subjects with varying degrees of renal impairment.
• The results of this study will allow confident dosing of sitaxsentan in individuals with renal impairment, and inform future studies.

Aim

To investigate the pharmacokinetic profile of a single 100-mg oral dose of sitaxsentan, a selective endothelin type A receptor antagonist, in subjects with normal and impaired renal function.

Methods

This was an open label, single oral dose study in subjects with normal [creatinine clearance (CrCL) ≥ 80 ml min⁻¹] and impaired renal function (mild renal impairment CrCL 51–80 ml min⁻¹, moderate impairment CrCL 31–50 ml min⁻¹, severe impairment CrCL ≤ 30 ml min⁻¹). All subjects received a dose of 100 mg sitaxsentan.

Results

Twenty-four subjects were enrolled, six in each of the normal and three renal impairment groups. The mean plasma sitaxsentan concentrations were comparable across the groups, as were the mean values for C_max (10.3–13.9 µg ml⁻¹), AUC_∞ (18.7–22.5 h µg⁻¹ ml⁻¹), oral clearance (CL/F, 82.3–94.9 ml min⁻¹), volume of distribution (Vz/F, 64.8–69.6 l) and elimination half-life (t_1/2, 8.6–9.6 h). There was substantial overlap among the four groups in the individual subject values for CL/F and Vz/F and no relationship between either of these parameters and CrCL.

Conclusion

After a single 100-mg oral dose of sitaxsentan there were no differences in its pharmacokinetics among subjects with normal or impaired renal function.     

Absolute bioavailability of imidafenacin after oral administration to healthy subjects

Aims

To investigate the absolute bioavailability of imidafenacin, a new muscarinic receptor antagonist, a single oral dose of 0.1 mg imidafenacin was compared with an intravenous (i.v.) infusion dose of 0.028 mg of the drug in healthy subjects.

Methods

Fourteen healthy male subjects, aged 21–45 years, received a single oral dose of 0.1 mg imidafenacin or an i.v. infusion dose of 0.028 mg imidafenacin over 15 min at two treatment sessions separated by a 1-week wash-out period. Plasma concentrations of imidafenacin and the major metabolites M-2 and imidafenacin-N-glucuronide (N-Glu) were determined. The urinary excretion of imidafenacin was also evaluated. Analytes in biological samples were measured by liquid chromatography tandem mass spectrometry.

Results

The absolute oral bioavailability of imidafenacin was 57.8% (95% confidence interval 54.1, 61.4) with a total clearance of 29.5 ± 6.3 l h⁻¹. The steady-state volume of distribution was 122 ± 28 l, suggesting that imidafenacin distributes to tissues. Renal clearance after i.v. infusion was 3.44 ± 1.08 l h⁻¹, demonstrating that renal clearance plays only a minor role in the elimination of imidafenacin. The ratio of AUC_t of both M-2 and N-Glu to that of imidafenacin was reduced after i.v. infusion from that seen after oral administration, suggesting that M-2 and N-Glu in plasma after oral administration were generated primarily due to first-pass metabolism. No serious adverse events were reported during the study.

Conclusions

The absolute mean oral bioavailability of imidafenacin was determined to be 57.8%. Imidafenacin was well tolerated following both oral administration and i.v. infusion.

What is already known about this subject

• The absolute bioavailability of imidafenacin in rats and dogs is 5.6% and 36.1%, respectively.
• The pharmacokinetic profiles of imidafenacin after oral administration have been revealed.
• Imidafenacin is primarily metabolized to metabolites by CYP3A4 and UGT1A4.

What this study adds

• The absolute bioavailability of imidafenacin in human is 57.8%.
• The pharmacokinetic profiles of imidafenacin after intravenous administration are revealed.
• The formation of metabolites in the plasma is caused mainly by first-pass effects.

     

Population pharmacokinetic and pharmacodynamic modelling of the effects of nicorandil in the treatment of acute heart failure

AIMS

The aims of the study were 1) to evaluate the pharmacokinetics of nicorandil in healthy subjects and acute heart failure (AHF) patients and 2) to evaluate the exposure-response relationship with pulmonary arterial wedge pressure (PAWP) in AHF patients and to predict an appropriate dosing regimen for nicorandil.

METHODS

Based on the data from two healthy volunteer and three AHF patient studies, models were developed to characterize the pharmacokinetics and pharmacodynamics of nicorandil. PAWP was used as the pharmacodynamic variable. An asymptotic exponential disease progression model was used to account for time dependent changes in PAWP that were not explained by nicorandil exposure. The modelling was performed using NONMEM version V.

RESULTS

The pharmacokinetics of nicorandil were characterized by a two-compartment model with linear elimination. CL, V1 and V2 in AHF patients were 1.96, 1.39 and 4.06 times greater than in healthy subjects. Predicted plasma concentrations were assumed to have an immediate concentration effect relationship on PAWP. An inhibitory E_max model with E_max of −11.7 mmHg and EC₅₀ of 423 µg l⁻¹ was considered the best relationship between nicorandil concentrations and PAWP. PAWP decreased independently of nicorandil exposure. This drug independent decline was described by an asymptotic decrease of 6.1 mmHg with a half-life of 5.3 h.

CONCLUSIONS

AHF patients have higher clearance and initial distribution volume of nicorandil compared with healthy subjects. The median target nicorandil concentration to decrease PAWP by 30% is predicted to be 748 µg l⁻¹, indicating that a loading dose of 200 µg kg⁻¹ and a maintenance dose of 400 µg kg⁻¹ h⁻¹ would be appropriate for the initial treatment of AHF.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Nicorandil injection is used for unstable angina and for acute heart failure in Japan.
• The pharmacokinetics of nicorandil following oral administration have been described in healthy subjects.

WHAT THIS STUDY ADDS

• This paper describes the differences in nicorandil pharmacokinetics between healthy subjects and acute heart failure patients.
• A population pharmacokinetic-pharmacodynamic model for nicorandil in acute heart failure patients is described using pulmonary artery wedge pressure as the biomarker.
• A rational guide for initial dosing of nicorandil to achieve a target effect on pulmonary artery wedge pressure was based on pharmacokinetic and pharmacodynamic principles.

     

Steady-state pharmacokinetics of the enantiomers of perhexiline in CYP2D6 poor and extensive metabolizers administered Rac-perhexiline

Aims

To determine the steady-state pharmacokinetics of perhexiline (PHX) enantiomers over one interdosing interval in CYP2D6 extensive and poor metabolizer (EM and PM, respectively) patients administered rac-PHX. To elucidate the processes responsible for enantioselectivity, particularly in PM patients.

Methods

Blood samples were taken over one interdosing interval from six EM and two PM patients at steady-state with respect to rac-PHX metabolism. Complete urine collections were taken from five EM patients. PHX concentrations in plasma and urine were determined with enantioselective high-performance liquid chromatography methods.

Results

EM patients had 16- and 10-fold greater median apparent oral clearances of (+)- and (−)-PHX, respectively, than PM patients (P < 0.05 for both) and required significantly larger doses of rac-PHX (69 vs. 4.2 µg kg⁻¹ h⁻¹, P < 0.05) to maintain therapeutic concentrations in plasma. Patient phenotypes were consistent with CYP2D6 genotypes. Both groups displayed enantioselective pharmacokinetics, with higher apparent oral clearances for (−)-PHX compared with (+)-PHX, although PM patients exhibited significantly greater enantioselectivity (P < 0.05). The renal clearance of PHX enantiomers was not enantioselective and accounted for <1% of the median apparent oral clearance of each enantiomer in EM patients. Assuming the same renal clearances for PM patients accounts for approximately 9 and 4% of their median apparent oral clearances of (+)- and (−)-PHX, respectively.

Conclusions

The enantioselective pharmacokinetics of PHX are primarily due to metabolism by CYP2D6 in EM patients. The mechanism responsible for the enantioselective pharmacokinetics of PHX in PM patients is unknown, but may be due to enantioselective biliary or intestinal excretion.

What is already known about this subject

• Perhexiline (PHX) is administered as a racemic mixture and exhibits enantioselective pharmacokinetics in both poor and extensive metabolizers of CYP2D6 (PM and EM, respectively).
• Extensive metabolism by CYP2D6 is primarily responsible for the observed enantioselectivity in EM, but the process responsible in PM is unknown.
• Analysis of the steady-state plasma concentration–time profiles of the enantiomers of PHX in PM and EM was undertaken in order to elucidate the observed enantioselectivity, particularly with respect to PM.

What this study adds

• This is the first study to examine the steady-state plasma concentration–time profiles of the enantiomers of PHX in EM and PM over the course of an interdosing interval.
• The apparent oral clearance of each enantiomer was calculated from their respective AUC rather than from trough concentrations and was enantioselective in both phenotypes, with higher apparent oral clearances of (−)-than (+)-PHX.
• Renal clearance, calculated for EM and subsequently assumed for PM, constitutes a greater proportion of the total apparent oral clearance of each enantiomer in PM than EM, but was not enantioselective and thus unable to explain the enantioselectivity observed in PM.

     

Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co-administered in healthy female subjects

AIM

To assess the two-way pharmacokinetic interaction between voriconazole and Ortho-Novum® 1/35, an oral contraceptive containing norethindrone 1 mg and ethinyl oestradiol 35 μg.

METHODS

In this open-label, three-period, fixed-sequence study, 16 healthy females received voriconazole (400 mg q12 h, day 1; 200 mg q12 h, days 2–4) (period 1), oral contraceptive (q24 h, days 12–32) (period 2), and combination voriconazole (400 mg q12 h, day 57; 200 mg q12 h, days 58–60) and oral contraceptive (q24 h, days 40–60) (period 3).

RESULTS

Voriconazole geometric mean AUC_τ and C_max increased 46% (12 682–18 495 ng h ml⁻¹; 90% confidence interval [CI] 32, 61) and 14% (2485–2840 ng ml⁻¹; 90% CI 3, 27), respectively, when co-administered with oral contraceptive vs. voriconazole alone. Ethinyl oestradiol geometric mean AUC_τ and C_max increased 61% (1031–1657 ng h ml⁻¹; 90% CI 50, 72) and 36% (119–161 ng ml⁻¹; 90% CI 28, 45), respectively, and norethindrone geometric mean AUC_τ and C_max increased 53% (116–177 ng h ml⁻¹; 90% CI 44, 64) and 15% (18–20 ng ml⁻¹; 90% CI 3, 28), respectively, during voriconazole co-administration vs. oral contraceptive alone. Neither ethinyl oestradiol nor norethindrone levels were reduced in subjects following voriconazole co-administration. Adverse events (AEs) were generally mild, occurring less in subjects receiving voriconazole alone (36 events) vs. oral contraceptive alone (88 events) or combination treatment (68 events); four subjects experienced a severe AE.

CONCLUSIONS

Co-administration of voriconazole and oral contraceptive increased systemic exposures of all analytes relative to respective monotherapy. Although generally safe and well tolerated, it is recommended that patients receiving co-administered voriconazole and oral contraceptive be monitored for development of AEs commonly associated with these medications.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Voriconazole, a broad-spectrum antifungal drug, is a substrate and inhibitor of CYP2C19 and CYP3A4 isozymes.
• Ethinyl oestradiol and norethindrone, components of the combination oral contraceptive drug Ortho-Novum® 1/35, also are substrates of cytochrome P450 CYP2C19 and CYP3A4 isozymes.
• Because co-administration of voriconazole and Ortho-Novum® 1/35 could potentially result in pharmacokinetic interactions that increase systemic exposure of one or both drugs to unsafe levels, clinical studies are needed to define better the two-way pharmacokinetic interaction between these drugs.

WHAT THIS STUDY ADDS

• Although co-administered voriconazole and oral contraceptive did result in increased systemic exposures of all three drugs relative to respective monotherapy, co-administered treatment was generally safe and well tolerated.
• It is recommended, however, that patients receiving co-administered voriconazole and oral contraceptives be monitored for the development of adverse events commonly associated with these medications.

     

The recovery time-course of CYP3A after induction by St John's wort administration

AIMS

To examine the recovery time course of CYP3A after enzyme induction by St John''s wort administration.

METHODS

The subjects were 12 healthy men, aged 20–33 years. On the first day, they received an oral dose of midazolam 5 mg without St John''s wort (day −14). From the next day, they took St John''s wort for 14 days. On the last day of St John''s wort treatment (day 0) and 3 and 7 days after completion of St John''s wort treatment (days 3 and 7), they received the same dose of midazolam. On each day, blood samples were obtained until 8 h after midazolam administration. Plasma concentrations of midazolam were measured by HPLC. Pharmacokinetic parameters of midazolam were determined using noncompartmental analysis.

RESULTS

Apparent oral clearance of midazolam was significantly increased after St John''s wort administration from 65.3 ± 8.4 l h⁻¹ (day −14) to 86.8 ± 17.3 l h⁻¹ (day 0). It returned to the control level 7 days after the completion of St John''s wort (day 7, 59.7 ± 3.8 l h⁻¹). No significant difference in the elimination half-life between the four periods of the study was observed. The changes in apparent oral clearance after St John''s wort discontinuation indicated that CYP3A activity recovers from enzyme induction with an estimated half-life of 46.2 h.

CONCLUSIONS

CYP3A activity induced by St John''s wort administration progressively returns to the basal level after approximately 1 week. This finding may provide useful information to avoid clinically significant interactions of St John''s wort with CYP3A substrates.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• St John''s wort causes the induction of CYP3A. Little is known about how long the effect remains after cessation of St John''s wort.

WHAT THIS STUDY ADDS

• The in vivo CYP3A activity returns progressively to the basal level approximately 1 week after cessation of St John''s wort administration

     

Mechanistic modelling of tesaglitazar pharmacokinetic data in subjects with various degrees of renal function--evidence of interconversion

AIMS

To develop a mechanistic pharmacokinetic (PK) model for tesaglitazar and its metabolite (an acyl glucuronide) following oral administration of tesaglitazar to subjects with varying renal function, and derive an explanation for the increased plasma exposure of tesaglitazar in subjects with impaired renal function.

METHODS

Data were from a 6-week study in subjects with renal insufficiency and matched controls undergoing repeated oral dosing with tesaglitazar (n = 41). Compartmental population PK modelling was employed to describe the PK of tesaglitazar and its metabolite, in plasma and urine, simultaneously. Two hypotheses were tested to investigate the increased exposure of tesaglitazar in subjects with renal functional impairment: tesaglitazar metabolism is correlated with renal function, or metabolite elimination is reduced in renal insufficiency, leading to increased hydrolysis (interconversion) to the parent compound via biliary circulation.

RESULTS

The hypothesis for interconversion was best supported by the data. The population PK model included first-order absorption, two-compartment disposition and separate renal (0.027 l h⁻¹) and metabolic (1.9 l h⁻¹) clearances for tesaglitazar. The model for the metabolite; one-compartment disposition with renal (saturable, V_max = 0.19 μmol l⁻¹ and K_m = 0.04 μmol l⁻¹) and nonrenal clearances (1.2 l h⁻¹), biliary secretion (12 h⁻¹) to the gut, where interconversion and reabsorption (0.8 h⁻¹) of tesaglitazar occurred.

CONCLUSION

A mechanistic population PK model for tesaglitazar and its metabolite was developed in subjects with varying degrees of renal insufficiency. The model and data give insight into the likely mechanism (interconversion) of the increased tesaglitazar exposure in renally impaired subjects, and separate elimination and interconversion processes without dosing of the metabolite.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Tesaglitazar, is predominantly metabolized (to an acyl glucuronide of the parent compound) and 20% of given dose is found unchanged in the urine.
• Acyl glucuronides are know to be unstable and can become hydrolysed back to parent compound, a phenomena called interconversion.

WHAT THIS STUDY ADDS

• A likely mechanism (interconversion) for the cause of the increased exposure of tesaglitazar in subjects with impaired renal function.
• A possible modelling framework to evaluate interconversion without dosing of the metabolite based on the simultaneous analysis of plasma and urine data from a group of subjects with varying renal function.
• A mechanistic understanding of the pharmacokinetic properties of tesaglitazar and its metabolite.

     

Lack of tacrolimus circadian pharmacokinetics and CYP3A5 pharmacogenetics in the early and maintenance stages in Japanese renal transplant recipients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Circadian variations of tacrolimus pharmacokinetics are controversial.
• Also, the pharmacokinetics has time-dependent variability, such as a decrease in oral clearance and increase in the dose-adjusted AUC after transplantation.
• Although the CYP3A5 polymorphism is associated with tacrolimus pharmacokinetics, differences in the influence of this gene on the pharmacokinetics between the early and maintenance stages have not yet been clarified.

WHAT THIS STUDY ADDS

• Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage with our designated-time administration strategy.
• Based on previous results and our own findings, the interval between food consumption and tacrolimus administration might influence the interindividual and interinstitutional variability of tacrolimus chronopharmacokinetics.
• The CYP3A5 polymorphism may be associated with the time-dependent changes in tacrolimus oral clearance.

AIMS

We investigated whether tacrolimus pharmacokinetics shows circadian variation and the influence of the CYP3A5 A6986G polymorphism on the pharmacokinetics in both the early and maintenance stages after renal transplantation.

METHODS

Tacrolimus was administered twice daily at specified times (09.00 and 21.00 h) throughout the pre- and post-transplant period according to the trough-targeting strategy. Fifty recipients with stable graft function were studied on day 28 and beyond 1-year post transplantation. Whole blood samples were collected prior to and 1, 2, 3, 4, 6, 9 and 12 h after both the morning and evening doses during hospitalization.

RESULTS

Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage [AUC_0–12 197.1 (95% confidence interval 182.9, 212.3) in daytime vs. 203.6 ng h ml⁻¹ (189.8, 217.4) in the night-time at day 28, 102.0 (92.1, 111.9) vs. 107.7 (97.9, 117.5) at 1 year, respectively]. In CYP3A5 *1 allele carriers (CYP3A5 expressers), body weight-adjusted oral clearance was markedly decreased from the early stage to the maintenance stage [0.622 (0.534, 0.709) to 0.369 l h⁻¹ kg⁻¹ (0.314, 0425)] compared with a smaller decrease [0.368 (0.305, 0.430) to 0.305 (0.217, 0.393)] in CYP3A5 non-expressers; however, the CYP3A5 genetic variation did not influence tacrolimus chronopharmacokinetics.

CONCLUSION

Equivalent daytime and night-time tacrolimus pharmacokinetics were achieved during both the early and maintenance stages with our specified-time administration strategy. The CYP3A5 polymorphism may be associated with the time-dependent changes in the oral clearance of tacrolimus, suggesting that genotyping of this polymorphism is useful for determining the appropriate dose of tacrolimus in both the early and maintenance stages after renal transplantation.     

Interaction between midazolam and clarithromycin in the elderly

AIM

To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrate midazolam and clarithromycin in the elderly.

METHODS

On day 1, 16 volunteers (eight male, eight female) aged 65–75 years weighing 59–112 kg received simultaneous doses of midazolam intravenously (i.v.) (0.05 mg kg⁻¹ over 30 min) and orally (p.o.) (3.5 mg of a stable isotope, ¹⁵N₃-midazolam). Starting on day 2, clarithromycin 500 mg was administered orally twice daily for 7 days. On day eight, i.v. and p.o. doses of midazolam were administered 2 h after the final clarithromycin dose. Serum and urine samples were assayed for midazolam, ¹⁵N₃-midazolam and metabolites by gas chromatography/mass spectometry.

RESULTS

Men and women exhibited similar i.v. (30.4 vs. 36.0 l h⁻¹) and p.o. (119 vs. 124 l h⁻¹) clearances of midazolam. Midazolam hepatic availability was significantly (P = 0.006) greater in men [0.79, 95% confidence interval (CI) 0.75, 0.84] than in women (0.66, 95% CI 0.59, 0.73), but midazolam intestinal availability (0.39 vs. 0.55) was not different. Following clarithromycin dosing, a significant decrease in systemic (33.2 l h⁻¹ to 11.5 l h⁻¹) and oral (121 l h⁻¹ to 17.4 l h⁻¹) midazolam clearance occurred. Oral, hepatic and intestinal availability was significantly increased after clarithromycin dosing from 0.34 to 0.72, 0.73 to 0.91 and 0.47 to 0.79, respectively. Clarithromycin administration led to an increase in the AUC of midazolam by 3.2-fold following i.v. dosing and 8.0-fold following p.o. dosing. Similar effects were observed for males and females.

CONCLUSIONS

Intestinal and hepatic CYP3A inhibition by clarithromycin significantly reduces the clearance of midazolam in the elderly.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Clarithromycin is a mechanism-based inhibitor of CYP3A that has been shown to inhibit midazolam hydroxylation in young, healthy subjects.
• Elderly persons exhibit altered metabolism of a variety of drugs, including clarithromycin.
• However, the consequences of increased exposure to an inhibitor drug on CYP3A activity have not been addressed.

WHAT THIS STUDY ADDS

• This study utilized intravenous and oral midazolam as in vivo probes to examine the effect of clarithromycin on intestinal and hepatic CYP3A activity.
• Although clarithromycin concentrations are greater in elderly individuals than in young, healthy volunteers, intestinal and hepatic CYP3A enzymes are inhibited to a similar extent as in the young.

     

Use of a sparse sampling study design to assess transfer of tramadol and its O-desmethyl metabolite into transitional breast milk

AIMS

To investigate the transfer of rac-tramadol and its rac-O-desmethyl metabolite into transitional milk, and assess unwanted effects in the breastfed infant.

METHODS

Tramadol HCl (100 mg six hourly) was administered to 75 breastfeeding mothers for postoperative analgesia on days 2–4 after Caesarian section. Milk and plasma samples were collected after administration of four or more doses. Rac-tramadol and rac-O-desmethyltramadol were measured by high performance liquid chromatography. Milk : plasma ratio (M : P) and infant doses were calculated by standard methods. The behavioural characteristics of the exposed breastfed infants and a matched control group of infants not exposed to tramadol were also studied.

RESULTS

At steady-state, mean (95% CI) M : P was 2.2 (2.0, 2.4) for rac-tramadol and 2.8 (2.5, 3.1) for rac-O-desmethyltramadol. The estimated absolute and relative infant doses were 112 (102, 122) μg kg⁻¹ day⁻¹ and 30 (28, 32) μg kg⁻¹ day⁻¹, and 2.24% (2.04, 2.44)% and 0.64% (0.59, 0.69)% for rac-tramadol and rac-O-desmethyltramadol, respectively. The exposed infants and control breastfed infants had similar characteristics, including Apgar scores at birth and Neurologic and Adaptive Capacity Scores.

CONCLUSIONS

The combined relative infant dose of 2.88% at steady-state was low. The similarity of NACS in exposed infants and controls suggests that there were no significant behavioural adverse effects. We conclude that short-term maternal use of tramadol during establishment of lactation is compatible with breastfeeding.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• There are presently no published data on tramadol transfer into breast milk or on its effects in the breastfed infant.

WHAT THIS STUDY ADDS

• We have provided quantitative data on the absolute and relative infant doses of rac-tramadol and it rac-O-desmethyl metabolite for the breastfed infant.
• We have also demonstrated a novel sparse sampling data collection method for investigating infant exposure via milk.

     

The influence of continuous venovenous haemodialysis on the pharmacokinetics of multiple oral moxifloxacin administration to patients with severe renal dysfunction

What is already known about this subject

• Although renal excretion is one important route of excretion of moxifloxacin and its metabolites, moxifloxacin pharmacokinetics are similar in patients with varying degrees of renal impairment (but not on dialysis) and in healthy subjects.

What this study adds

• This study showed that moxifloxacin pharmacokinetics are comparable in patients with severe renal failure requiring haemodialysis and in healthy subjects and patients with impaired renal function not on dialysis.
• No dose adjustments are required for haemodialysis patients on oral moxifloxacin therapy.

Aim

We investigated single dose and steady-state pharmacokinetics of moxifloxacin in eight venovenous haemodialysis patients.

Methods

Plasma, dialysate and urine pharmacokinetic parameters for moxifloxacin and its main metabolites were calculated after single and multiple (7 days) dosing with 400 mg day⁻¹.

Results

Moxifloxacin pharmacokinetics after a single dose and at steady state (multidose day 7) were comparable in patients with impaired renal function and healthy subjects (geometric mean/%CV AUC mg l⁻¹ h single dose 37.0/24.3 in haemodialysis patients vs. 29.8/22.6 in healthy subjects, 95% CI for ratio of haemodialysis patients to healthy subjects 99.34%, 154.60%; steady state 40.4/29.1 haemodialysis patients vs. 33.9/20.1 in healthy subjects, 95% CI for ratio of haemodialysis patients to healthy subjects 90/39%, 156.93%). In haemodialysis patients plasma concentrations of moxifloxacin at steady-state were elevated compared with those after a single 400 mg dose (AUC mg l⁻¹ h, geometric mean/%CV, 40.4/29.1) compared with 37.0/24.3; 95% CI for ratio of steady-state to single dose 87.29%, 136.52%, as were concentrations of metabolite M1 3.21/34.6 compared with 2.02/45.3, 95% CI for ratio of steady state to single dose 14.21%, 175.07%. Haemodialysis cleared about 9% of the dose as unchanged moxifloxacin.

Conclusions

No dose adjustments are required for venovenous haemodialysis patients on oral moxifloxacin therapy.     

Contribution of the M3 muscarinic receptors to the vasodilator response to acetylcholine in the human forearm vascular bed

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Available evidence suggests that the M₃ receptor on endothelial cells is responsible for acetylcholine (Ach)-dependent vasodilatation.
• Data from human studies only provide indirect evidence for this, and results are more difficult to interpret.

WHAT THIS STUDY ADDS

• This study used the new M₃ receptor antagonist darifenacin as a pharmacological ‘tool’ to investigate the role of M₃ receptor in the human forearm circulation.
• It provides evidence for a major role for the M₃ receptors in ACh-dependent vasodilatation in the forearm vascular bed.

AIMS

Acetylcholine (ACh) is a muscarinic agonist that causes receptor-mediated, endothelium-dependent vasodilatation in the forearm vasculature. Previous indirect evidence suggests this effect may be mediated by muscarinic M₃ receptors. Darifenacin is a recently developed antimuscarinic drug with greater M₃ selectivity, and our main objective was to investigate whether darifenacin affects dose-dependent vasodilatation to ACh in the forearm circulation.

METHODS

Healthy subjects were enrolled in two studies designed to assess the effects of atropine and darifenacin on the forearm blood flow (FBF) response to ACh.

RESULTS

In both studies ACh caused similar dose-dependent vasoditation in the forearm vasculature. In study I (5 subjects), the FBF response to ACh was largely attenuated by pretreatment with the nonselective muscarinic antagonist atropine. In study II (10 subjects), oral administration of darifenacin 15 mg for 1 week significantly reduced the FBF dose-dependent response to ACh 20 µg min⁻¹ {mean difference from placebo 5.8 [95% confidence interval (CI) 3.1, 8.7] ml min⁻¹ per 100 ml of forearm volume, P < 0.001} and to ACh 60 µg min⁻¹[mean difference from placebo 5.9 (95% CI 3.1, 8.7) ml min⁻¹ per 100 ml of forearm volume, P < 0.001]. After darifenacin, the AUC of change in FBF from baseline was reduced by almost 50% compared with placebo.

CONCLUSIONS

These results suggest that, in the forearm vasculature, muscarinic M₃ receptors play a major role in ACh-induced endothelium-mediated vasodilatation.     

Transfer of chloroquine and desethylchloroquine across the placenta and into milk in Melanesian mothers

AIMS

To investigate the transfer of chloroquine and its major bioactive metabolite desethylchloroquine across the placenta and into breast milk.

METHODS

In Papua New Guinea, chloroquine (CQ; 25 mg base kg⁻¹) is recommended for prophylaxis of malaria during pregnancy, and at the Alexishafen Health Centre women are routinely prescribed CQ at the time of delivery. Fetal-cord and maternal serum samples were collected at delivery (n = 19) and milk samples were collected from day 3 to day 17–21 after delivery (n = 16). CQ and its primary active metabolite desethylchloroquine (DECQ) were quantified by high-performance liquid chromatography. For both CQ and DECQ cord/maternal ratios (C/M) were calculated to characterize placental transfer, and infant exposure via milk was estimated by standard methods.

RESULTS

The median (interquartile range) C/M was 1.1 (0.9, 1.6) for CQ and 1.2 (0.5, 1.8) for DECQ. The average concentration in milk over the time of sampling was 167 μg l⁻¹ (27, 340) for CQ and 54 μg l⁻¹ (22, 106) for DECQ. Estimated absolute and relative infant doses were 34 μg kg⁻¹ day⁻¹ (7, 50) and 15 μg kg⁻¹ day⁻¹ (4, 26), and 2.3% (0.5, 3.6) and 1.0% (0.4, 2.0) for CQ and DECQ (as CQ equivalents), respectively.

CONCLUSION

Infant exposure to CQ and DECQ during pregnancy will be similar to that in the maternal circulation, and dependent on maternal dose and frequency. The median CQ + DECQ relative infant dose of 3.2% (as CQ equivalents) was low, confirming that use of CQ during lactation is compatible with breastfeeding.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The literature on placental and milk transfer of chloroquine and its major bioactive metabolite desethylchloroquine is sparse and incomplete.

WHAT THIS STUDY ADDS

• We have provided data on the transplacental transfer of chloroquine and desethylchloroquine in Melanesian women (n = 19), measured transfer of these drugs into breast milk (n = 16) and estimated absolute and relative infant doses for the breastfed infant.
• The data for desethylchloroquine are novel.
• In all three areas we have significantly increased both quantity and quality of the available database.

     

Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients

What is already known about this subject

• In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability.
• Some studies of population pharmacokinetics have already been conducted in liver transplant recipients and in paediatric patients.

What this study adds

• Our work determined population pharmacokinetic parameters, in particular bioavailability, in kidney transplant recipients and the relative importance of factors influencing the disposition of tacrolimus.
• Clearance was modelled and days postoperation and corticosteroids dose were significant covariates.

Aims

The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics.

Methods

The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring.

Results

A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 ± 0.2 l h⁻¹. Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 ± 0.5 days, with a maximal value of 5.6 l h⁻¹. Moreover clearance increased by approximately 1.6 fold (range 0.5–1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 ± 13 l kg⁻¹) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F.

Conclusions

The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.     

An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study

AIMS

To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety.

METHODS

Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg⁻¹ of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure.

RESULTS

Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h⁻¹ (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)^1.49. AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l⁻¹ h (or AUC3D < 900 mg l⁻¹ h) and in 91% when AUC1D > 600 mg l⁻¹ h (or AUC3D > 900 mg l⁻¹ h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated.

CONCLUSIONS

To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg⁻¹ for neonates younger than 70 h, 14, 7, 7 mg kg⁻¹ for neonates between 70 and 108 h and 18, 9, 9 mg kg⁻¹ for neonates between 108 and 180 h.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates.
• Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age.

WHAT THIS STUDY ADDS

• A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen.
• Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age.
• A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced.
• Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates.

     

Pyrazinamide blood concentrations in children suffering from tuberculosis: a comparative study at two doses

Aims

To evaluate the pharmacokinetics and pharmacodynamic indices of pyrazinamide at doses of 15 and 25 mg kg⁻¹ in children suffering from tuberculosis.

Methods

Twenty children with tuberculosis received pyrazinamide at a single dose of 25 mg kg⁻¹ (group I) and 15 mg kg⁻¹ (group II). Serial blood samples were collected and the drug concentrations were analyzed spectrophotometrically. The pharmacokinetic parameters were calculated and the duration of time for which pyrazinamide concentrations in serum remained above the pyrazinamide inhibitory concentrations of 20 μg ml⁻¹ and 25 μg ml⁻¹ was studied.

Results

The mean peak serum concentration was 42.4 ± 3.3 μg ml⁻¹ (95% CI ± 6.5) and 38.6 ± 3.9 μg ml⁻¹ (95% CI ± 7.7) in groups I and II, respectively. The elimination half-life was 9.3 ± 1.3 h and 10.5 ± 2.3 h (P = 0.6) and clearance was 0.06 ± 0.01 l h⁻¹ kg⁻¹ and 0.04 ± 0.01 l h⁻¹ kg⁻¹ (P = 0.08) in groups I and II, respectively. Pharmacokinetic parameters and PKPD indices were comparable with both the doses.

Conclusions

The study indicates that comparable serum concentrations of pyrazinamide are attained with 25 mg kg⁻¹ and 15 mg kg⁻¹ doses in children. The elimination half-life was longer and volume of distribution greater in children than in the adult population.

What is already known about this subject

• Pyrazinamide is recommended in doses varying from 15 to 40 mg kg⁻¹. The most commonly used average daily dose is 25 mg kg⁻¹. Its use is associated with dose dependent hepatotoxicity.
• Lower doses are not used because of lack of pharmacokinetic data especially in children. There is only one detailed study of pyrazinamide in children at a dose of 35 mg kg⁻¹.

What this study adds

• This is the first study evaluating serum concentrations of pyrazinamide in children at a dose of 15 mg kg⁻¹ which is on the lower side of the recommended dose. The study also compared the serum concentrations and pharmacokinetics achieved with this dose with the widely used dose of 25 mg kg⁻¹ in children suffering from tuberculosis.
• The pharmacokinetics and pharmacodynamic indices of pyrazinamide were comparable with the 25 and 15 mg kg⁻¹ doses.