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.     

Pharmacokinetics and clinical efficacy of lorazepam in children with severe malaria and convulsions

AIM

To investigate the pharmacokinetics and clinical efficacy of intravenous (i.v.) and intramuscular (i.m.) lorazepam (LZP) in children with severe malaria and convulsions.

METHODS

Twenty-six children with severe malaria and convulsions lasting ≥5 min were studied. Fifteen children were given a single dose (0.1 mg kg⁻¹) of i.v. LZP and 11 received a similar i.m. dose. Blood samples were collected over 72 h for determination of plasma LZP concentrations. Plasma LZP concentration–time data were fitted using compartmental models.

RESULTS

Median [95% confidence interval (CI)] LZP concentrations of 65.1 ng ml⁻¹ (50.2, 107.0) and 41.4 ng ml⁻¹ (22.0, 103.0) were attained within median (95% CI) times of 30 min (10, 40) and 25 min (20, 60) following i.v. and i.m. administration, respectively. Concentrations were maintained above the reported therapeutic concentration (30 ng ml⁻¹) for at least 8 h after dosing via either route. The relative bioavailability of i.m. LZP was 89%. A single dose of LZP was effective for rapid termination of convulsions in all children and prevention of seizure recurrence for >72 h in 11 of 15 children (73%, i.v.) and 10 of 11 children (91%, i.m), without any clinically apparent respiratory depression or hypotension. Three children (12%) died.

CONCLUSION

Administration of LZP (0.1 mg kg⁻¹) resulted in rapid achievement of plasma LZP concentrations within the reported effective therapeutic range without significant cardiorespiratory effects. I.m administration of LZP may be more practical in rural healthcare facilities in Africa, where venous access may not be feasible.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Lorazepam (LZP) may be a more useful anticonvulsant to stop convulsions in children with severe malaria (SM) than diazepam, since it has a longer duration of action and can be given by other routes, such as intramuscular (i.m.).
• There are no studies describing both the pharmacoknetics and clinical efficacy of LZP in African children, particularly those with SM.
• We have undertaken a study with LZP, administered either intravenously (i.v.) or i.m., to children with SM and convulsions in order to describe and compare the pharmacokinetic profiles of LZP following administration via both routes and determine whether the currently recommended dose of LZP (0.1 mg kg⁻¹) is effective in terminating convulsions in this group.

WHAT THIS STUDY ADDS

• Administration of LZP (i.v. or i.m.) at the currently recommended dose (0.1 mg kg⁻¹) resulted in rapid achievement of plasma LZP concentrations within the reported effective therapeutic range without clinically significant cardiorespiratory effects.
• A single dose of LZP was effective in the rapid termination of convulsions in all children, and prevention of seizure recurrence for >72 h in 11 of 15 (73%) children and 10 of 11 (91%) children after i.v. and i.m. administration, respectively.

     

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 pharmacokinetics and pharmacodynamics of cisatracurium in critically ill patients with severe sepsis

AIM

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium in critically ill patients with severe sepsis.

METHODS

Blood samples were collected before and over 8 h after a single bolus dose of cisatracurium 0.1 mg kg⁻¹. Neuromuscular block was assessed by accelerometric peripheral nerve stimulation (TOF Watch). Plasma concentration and neuromuscular block data were fitted using population analysis.

RESULTS

Steady-state volume of distribution was determined to be 111 ± 71 ml kg⁻¹ and plasma clearance was 5.2 ± 1.8 ml min⁻¹ kg⁻¹ in these patients with greater inter-patient variability compared with other populations. The time to maximum block (8.3 ± 2.9 min) and delay time of transferring from central to effect compartment (17.2 min) was much longer, while the maximum block (95.0 ± 6.3%) was less compared with those in other patient populations. The effect compartment concentration resulting in 50% of maximum effect (128 ± 58 ng ml⁻¹) was larger than previously described.

CONCLUSIONS

This study suggests that standard dosing of cisatracurium in patients with severe sepsis results in a slower patient response with a reduced effect. Use of a larger dose may overcome this reduced delayed response.     

Dose-effect study of domperidone as a galactagogue in preterm mothers with insufficient milk supply, and its transfer into milk

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Domperidone is an effective treatment for some mothers with insufficient milk supply.
• However, dose–effect data are not available, and the safety of domperidone use in both mother and infant has been questioned.

WHAT THIS STUDY ADDS

• Domperidone only increases milk production in about two-thirds of preterm mothers with insufficient milk supply.
• On average, the responders showed increasing levels of milk production with dose escalation from 30 mg to 60 mg daily.
• The amount of domperidone that transferred into breast milk was very low, and the risk to the breastfed infant is minimal.

AIMS

To investigate the possibility of a dose–response relationship for the use of domperidone in treating insufficient milk supply in mothers of preterm infants, and to quantify the exposure of the breastfed infant to domperidone.

METHODS

Six preterm mothers received domperidone (30 mg daily or 60 mg daily) in a double-blind, randomized, crossover trial. Milk production and serum prolactin were measured before and during the trial, and domperidone concentration in milk was measured during drug treatment.

RESULTS

For milk production, two of the mothers were ‘nonresponders’, whereas the other four were ‘responders’ and showed a significant increase in milk production from 8.7 ± 3.1 g h⁻¹ in the run-in phase (mean ± SEM), 23.6 ± 3.9 g h⁻¹ for the 30-mg dose (P = 0.0217) and 29.4 ± 6.6 g h⁻¹ for the 60-mg dose (P = 0.0047). In all participants, serum prolactin was significantly increased for both doses, but the response was not dose dependent. Median (interquartile range) domperidone concentrations in milk over a dose interval at steady-state were 0.28 µg l⁻¹ (0.24–0.43) and 0.49 µg l⁻¹ (0.33–0.72) for the 30-mg and 60-mg doses, respectively. The mean relative infant dose was 0.012% at 30 mg daily and 0.009% at 60 mg daily.

CONCLUSION

In one-third of mothers, domperidone did not increase milk production. In the remainder, milk production increased at both domperidone doses, and there was a trend for a dose–response relationship. The amount of domperidone that transfers into milk was extremely low, and infant exposure via breastfeeding was not considered to be significant.     

Multiple-dose pharmacokinetics of peginterferon alfa-2b in patients with renal insufficiency

What is already known about this subject?

• Current therapy for hepatitis C typically consists of pegylated interferon (PEG-IFN) alfa in combination with ribavirin.
• Pegylation of IFN alfa-2b confers a 10-fold increase in elimination half-life and a 30% reduction in volume of distribution compared with non-PEG-IFN alfa-2b.
• A single-dose pharmacokinetic study conducted in patients with chronic renal dysfunction has shown that renal elimination accounts for 30% of total PEG-IFN alfa-2b clearance and that PEG-IFN alfa-2b exposure increases with severity of renal insufficiency.

What this study adds

• Because the primary mechanism of IFN clearance is catabolism in the kidney, appropriate dosing of IFN-based therapies in patients with renal insufficiency is an important issue.
• This multiple-dose pharmacokinetic study shows that exposure to PEG-IFN alfa-2b is increased in patients with renal insufficiency, suggesting that doses of the drug should be reduced by 50% in patients with severe renal insufficiency and by 25% in those with moderate insufficiency.
• PEG-IFN alfa-2b was well tolerated in all patient groups during the 4-week treatment period, with similar adverse events occurring in patients with renal insufficiency and in those with normal renal function.

Aim

To evaluate the safety, tolerability and multiple-dose pharmacokinetics of pegylated interferon (PEG-IFN) alfa-2b in patients with moderate or severe renal insufficiency and in those with normal renal function.

Methods

In an open-label study, subjects with normal renal function (creatinine clearance >80 ml min⁻¹ per 1.73 m²) and patients with moderate (30–50 ml min⁻¹ per 1.73 m²) or severe (10–29 ml⁻¹ min⁻¹ per 1.73 m²) renal impairment received weekly injections of PEG-IFN alfa-2b (1.0 µg kg⁻¹) for 4 weeks. Safety assessments were made before each injection and blood samples were taken up to 168 h after the final dose.

Results

Renal insufficiency increased PEG-IFN alfa-2b exposure. Area under the curve for 0–τ (dosing interval of 168 h), AUC_τ, was increased 30% and 120% in patients with moderate or severe renal insufficiency, respectively. Mean maximum serum concentration was almost doubled in patients with severe insufficiency [1305.8 pg ml⁻¹; 95% confidence interval (CI) 825, 1786] compared with subjects with normal renal function (731.4 pg ml⁻¹; 95% CI 407, 1056), whereas the apparent volume of distribution was reduced (0.80 l kg⁻¹vs. 1.28 l kg⁻¹, respectively). Elimination half-life was extended in patients with moderate and severe renal insufficiency (65.6 h and 64.9 h, respectively) compared with subjects with normal renal function (51.5 h). Significant differences were observed in the AUC and C_max values of patients with severe renal dysfunction, compared with those who had normal renal function (P< 0.05; Kruskal–Wallis test). PEG-IFN alfa-2b was well tolerated and adverse events were similar in both treatment groups.

Conclusions

Exposure to PEG-IFN alfa-2b is increased in patients with renal insufficiency, suggesting that doses of the drug should be reduced by 50% in patients with severe renal insufficiency and by 25% in those with moderate insufficiency.     

Population pharmacokinetics of oral diclofenac for acute pain in children

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Diclofenac is an effective oral analgesic for acute postoperative pain. In adults 25 mg is half as effective as 50 mg, but 50 mg and 100 mg are similarly effective (ceiling effect). Diclofenac has linear pharmacokinetics in this range.
• Diclofenac is frequently used ‘off-label’ in children for acute pain but optimum dosing is unclear (dosing of diclofenac in clinical paediatric studies ranges from 0.5–2.5 mg kg⁻¹). There is currently no licensed oral paediatric formulation of diclofenac.

WHAT THIS STUDY ADDS

• Using a new diclofenac oral suspension, a dose of 1 mg kg⁻¹ in children aged 1 to 12 years gives a similar exposure to 50 mg in adults; paediatric patients are unlikely to benefit from higher doses.

AIMS

To develop a population pharmacokinetic model for a new diclofenac suspension (50 mg 5 ml⁻¹) in adult volunteers and paediatric patients, and recommend a dose for acute pain in children.

METHODS

Blood samples were drawn at the start and end of surgery, and on removal of the venous cannula from 70 children (aged 1 to 12 years, weight 9 to 37 kg) who received a preoperative oral 1 mg kg⁻¹ dose; these were pooled with rich (14 post-dose samples) data from 30 adult volunteers. Population pharmacokinetic modelling was undertaken with NONMEM. The optimum adult dose of diclofenac for acute pain is 50 mg. Simulation from the final model was performed to predict a paediatric dose to achieve a similar AUC to 50 mg in adults.

RESULTS

A total of 558 serum diclofenac concentrations from 100 subjects was used in the pooled analysis. A single disposition compartment model with first order elimination and dual absorption compartments was used. The estimates of CL/F and V_D/F were 53.98 l h⁻¹ 70 kg⁻¹ and 4.84 l 70 kg⁻¹ respectively. Allometric size models appeared to predict adequately changes in CL and V_D with age. Of the simulated doses investigated, 1 mg kg⁻¹ gave paediatric AUC_{(0, 12 h)} to adult 50 mg AUC_{(0, 12 h)} ratios of 1.00, 1.08 and 1.18 for ages 1–3, 4–6 and 7–12 years respectively.

CONCLUSIONS

This study has shown 1 mg kg⁻¹ diclofenac to produce similar exposure in children aged 1 to 12 years as 50 mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from higher doses.     

Population pharmacokinetics and dose simulation of carvedilol in paediatric patients with congestive heart failure

Aims

To investigate the ontogeny of carvedilol pharmacokinetics and to develop an age-appropriate carvedilol dosing strategy for paediatric patients.

Methods

Data were derived from a prospective, nonplacebo-controlled study of carvedilol for the treatment of paediatric patients with congestive heart failure and analysed using a nonlinear mixed-effects modelling approach (NONMEM, Version V 1.1). The population pharmacokinetic model was further utilized for simulations of different carvedilol dosing strategies.

Results

Four hundred and eighty carvedilol plasma concentrations of 41 patients (0.1–19.3 years; median 3.5) were included in the analysis. A two-compartment model with first-order absorption and absorption lag served as structural model. Weight and age were the most important covariates for carvedilol pharmacokinetics. The weight-adjusted clearance was highest for the younger patients with 2.7 l h⁻¹ kg⁻¹ for a 1-year-old patient compared with 0.7 l h⁻¹ kg⁻¹ for a 19.3-year-old patient. Dose simulations revealed that the area under the plasma concentration–time curve (AUC) as a measure of drug exposure increased with age despite constant doses with respect to body weight. For infants (28 days to 23 months), children (2–11 years) and adolescents (12–15 years) daily doses of 3, 2 and 1 mg kg⁻¹, administered in two or three discrete doses, were necessary to reach an exposure comparable to adults receiving 0.7 mg kg⁻¹ day⁻¹.

Conclusion

The ontogeny of carvedilol pharmacokinetics in paediatric patients depends on age and weight. Dose simulations revealed that younger patients have to be treated with higher doses with respect to body weight to reach the same exposure as adults.

What is already known about this subject

• Applying in silico tools such as population pharmacokinetic analysis and simulation will help to find adequate dosing strategies and increase the probability of success for a randomized controlled trial.
• Up to now, for carvedilol in paediatric patients with congestive heart failure (CHF) the dose has been linearly extrapolated from adults, but the results with this dosing strategy are ambiguous.
• Further trials are necessary to establish carvedilol for paediatric patients with CHF.

What this study adds

• Carvedilol pharmacokinetics in paediatric patients with CHF depends on the weight and age of the patient.
• Therefore, the drug exposure differs substantially between patients of different ages receiving the same dose with respect to body weight.
• Simulations revealed that an age-adjusted carvedilol dosing strategy with higher doses for younger patients with respect to body weight is preferable to a uniform one.

     

Pharmacokinetics and clinical efficacy of midazolam in children with severe malaria and convulsions

AIM

To investigate the pharmacokinetics and clinical efficacy of intravenous (IV), intramuscular (IM) and buccal midazolam (MDZ) in children with severe falciparum malaria and convulsions.

METHODS

Thirty-three children with severe malaria and convulsions lasting ≥5 min were given a single dose of MDZ (0.3 mg kg⁻¹) IV (n = 13), IM (n = 12) or via the buccal route (n = 8). Blood samples were collected over 6 h post-dose for determination of plasma MDZ and 1′-hydroxymidazolam concentrations. Plasma concentration–time data were fitted using pharmacokinetic models.

RESULTS

Median (range) MDZ C_max of 481 (258–616), 253 (96–696) and 186 (64–394) ng ml⁻¹ were attained within a median (range) t_max of 10 (5–15), 15 (5–60) and 10 (5–40) min, following IV, IM and buccal administration, respectively. Mean (95% confidence interval) of the pharmacokinetic parameters were: AUC(0,∞) 596 (327, 865), 608 (353, 864) and 518 (294, 741) ng ml⁻¹ h; V_d 0.85 l kg⁻¹; clearance 14.4 ml min⁻¹ kg⁻¹, elimination half-life 1.22 (0.65, 1.8) h, respectively. A single dose of MDZ terminated convulsions in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration. Four children (one in the IV, one in the IM and two in the buccal groups) had respiratory depression.

CONCLUSIONS

Administration of MDZ at the currently recommended dose resulted in rapid achievement of therapeutic MDZ concentrations. Although IM and buccal administration of MDZ may be more practical in peripheral healthcare facilities, the efficacy appears to be poorer at the dose used, and a different dosage regimen might improve the efficacy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Midazolam (MDZ), a water-soluble benzodiazepine, can be administered via several routes, including intravenously (IV), intramuscularly (IM) and buccal routes to terminate convulsions. It may be a suitable alternative to diazepam to stop convulsions in children with severe malaria, especially at peripheral healthcare facilities. The pharmacokinetics of MDZ have not been described in African children, in whom factors such as the aetiology and nutritional status may influence the pharmacokinetics.

WHAT THIS STUDY ADDS

• Administration of MDZ (IV, IM, or buccal) at the currently recommended dose (0.3 mg kg⁻¹) resulted in rapid achievement of median maximum plasma concentrations of MDZ within the range 64–616 ng ml⁻¹, with few clinically significant cardio-respiratory effects. A single dose of MDZ rapidly terminated (within 10 min) seizures in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration, respectively. Although IM and buccal MDZ may be the preferred treatment for children in the pre-hospital settings the efficacy appears to be poorer.

     

The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole

AIMS

Sotrastaurin is an immunosuppressant that reduces T-lymphocyte activation via protein kinase C inhibition. The effect of CYP3A4 inhibition by ketoconazole on the pharmacokinetics of sotrastaurin, a CYP3A4 substrate, was investigated.

METHODS

This was a two-period, single-sequence crossover study in 18 healthy subjects. They received a single 50 mg oral dose of sotrastaurin in period 1 followed by a 14-day inter-treatment phase. In period 2 they received ketoconazole 200 mg twice daily for 6 days and a single 50 mg dose of sotrastaurin on the fourth day of ketoconazole administration.

RESULTS

Co-administration of single-dose sotrastaurin during steady-state ketoconazole increased sotrastaurin C_max by 2.5-fold (90% confidence interval 2.2, 2.9) from 285 ± 128 to 678 ± 189 ng ml⁻¹ and increased AUC by 4.6-fold (4.1, 5.2) from 1666 ± 808 to 7378 ± 3011 ng ml⁻¹ h. Sotrastaurin half-life was nearly doubled from 5.9 ± 1.7 to 10.6 ± 2.5 h. The AUC of the active metabolite N-desmethyl-sotrastaurin was increased by 6.8-fold. Sotrastaurin did not alter ketoconazole steady-state predose plasma concentrations.

CONCLUSIONS

The strong CYP3A4 inhibitor ketoconazole increased sotrastaurin AUC by 4.6-fold. A compensatory reduction in the dose of sotrastaurin is warranted when strong CYP3A4 inhibitors are co-administered.     

Fluvoxamine pharmacokinetics in healthy elderly subjects and elderly patients with chronic heart failure

AIMS

To investigate the effects of age and chronic heart failure (CHF) on the oral disposition kinetics of fluvoxamine.

METHODS

A single fluvoxamine dose (50 mg) was administered orally to 10 healthy young adults, 10 healthy elderly subjects and 10 elderly patients with CHF. Fluvoxamine concentration in plasma was measured for up to 96 h.

RESULTS

With the exception of apparent distribution volume, ageing modified all main pharmacokinetic parameters of fluvoxamine. Thus, peak concentration was about doubled {31 ± 19 vs. 15 ± 9 ng ml⁻¹; difference [95% confidence interval (CI)] 16 (3, 29), P < 0.05}, and area under the concentration–time curve was almost three times higher [885 ± 560 vs. 304 ± 84 ng h ml⁻¹; difference (95% CI) 581 (205, 957), P < 0.05]; half-life was prolonged by 63% [21.1 ± 6.2 vs. 12.9 ± 6.4 h; difference (95% CI) 8.2 (2.3, 14.1), P < 0.01], and oral clearance was halved (1.12 ± 0.77 vs. 2.25 ± 0.66 l h⁻¹ kg⁻¹; difference (95% CI) −1.13 (−1.80, −0.46), P < 0.001]. A significant inverse correlation was consistently observed between age and oral clearance (r=−0.67; P < 0.001). The coexistence of CHF had no significant effect on any pharmacokinetic parameters in elderly subjects.

CONCLUSIONS

Ageing results in considerable impairment of fluvoxamine disposition, whereas CHF causes no significant modifications. Therefore, adjustment of initial dose and subsequent dose titrations may be required in elderly subjects, whereas no further dose reduction is necessary in elderly patients with CHF.     

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.     

Formulation of long-acting nifedipine tablets influences the heart rate and sympathetic nervous system response in hypertensive patients

AIMS

The haemodynamic responses to nifedipine vary between short- and long-acting formulations. However, the latter have not been compared despite marked differences in their constitution. Our 1-month randomized, crossover study was designed to compare the 30-mg osmotic, constant-release nifedipine gastrointestinal therapeutic system (N-GITS) with an encapsulated mini-tablet Coracten XL.

METHODS

Forty-four hypertensive patients aged 63 ± 7 years were studied. The formulation was changed on day 15 and (for a single dose) day 30. At days 0, 14, 15, 29 and 30, patients were monitored for 6 h after dosing, during which blood pressure (BP), heart rate (HR) and plasma levels of norepinephrine (NE) and nifedipine were measured. The primary outcome was the difference in plasma NE between formulations at the time of peak nifedipine level.

RESULTS

Systolic BP decreased rapidly after the first dose of Coracten, achieving nadir at 5 h. HR rose by 1.2 ± 8.8 beats min⁻¹. After N-GITS HR fell by 2.4 ± 7.7 beats min⁻¹ (P = 0.159). Plasma NE was higher in the Coracten- (480 ± 38.3 pg ml⁻¹) than N-GITS-treated patients (343 ± 75.0 pg ml⁻¹) at the time of peak nifedipine concentrations (4 and 5 h, respectively) and their change from baseline was significantly (P = 0.0046) different. A similar difference between the drugs was seen again at days 15 and 30, at 5 h after switching formulations.

CONCLUSIONS

This study suggests that two different formulations of once-daily nifedipine result in different BP and plasma NE responses, and that switching between formulations causes opposite effects upon the sympathetic nervous response to falling BP.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Pharmacokinetic and pharmacodynamics studies are usually carried out separately with theoretical linking or interpretations.
• The pharmacokinetics of short- vs. long-acting formulations of nifedipine is well known, but the pharmacokinetics of different once-a-day formulations of nifedipine is generally not well known by the practising physician.

WHAT THIS STUDY ADDS

• This study provides practical patient-based information linking pharmacokinetics to pharmacodynamics in one of the target populations of patients, those with hypertension, who might receive the two different drugs.

     

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.     

Prolonged pharmacodynamic effects of S-0139, an intravenously administered endothelin A (ETA) antagonist, in the human forearm blood flow model

AIMS

To estimate the pharmacologically active dose range of a new investigational compound S-0139, a selective endothelin A (ET_A) receptor antagonist, in man, and to examine the duration of its pharmacodynamic effect.

METHODS

Venous occlusion plethysmography was performed to assess changes in forearm blood flow following intra-brachial administration of endothelin-1 (ET-1). ET_A antagonists have been shown to block ET-1-induced vasoconstriction in this model. The study was conducted in three parts: (1) a pilot study to explore dose–response (dose range 0.08–13.33 µg kg⁻¹ min⁻¹), (2) a randomized study to confirm dose–response (placebo, 2.5, 6.67 and 15 µg kg⁻¹ min⁻¹), and (3) a delayed administration study (15.7 µg kg⁻¹ min⁻¹) to explore the duration of the pharmacodynamic effect. In all studies a 3-h infusion of S-0139 was given and during the last 90 min of the infusion, ET-1 was infused concurrently for 90 min. In study (3) a second ET-1 infusion was given starting 3 h after completion of the first.

RESULTS

Intravenously administered S-0139 resulted in significant inhibition of ET-1-induced vasoconstriction in the forearm (plasma concentration 800–2000 ng ml⁻¹). In the delayed administration study, the same extent of inhibition was still present when ET-1 was administered 3 h after the end of infusion of S-0139, even though the S-0139 plasma concentrations (mean 17 ng ml⁻¹) were well below pharmacologically active concentrations as determined in studies 1 and 2.

CONCLUSIONS

S-0139 dose-dependently blocks ET-1-mediated vasoconstriction in the forearm and has a prolonged duration of effect beyond that expected from its pharmacokinetic profile.     

No significant effect of SLCO1B1 polymorphism on the pharmacokinetics of rosiglitazone and pioglitazone

AIMS

To examine possible effects of polymorphism in the SLCO1B1 gene, encoding the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1, on the pharmacokinetics of rosiglitazone and pioglitazone in a prospective genotype panel study.

METHODS

Sixteen healthy volunteers with the homozygous SLCO1B1 c.521TT genotype (controls), 12 with the heterozygous c.521TC genotype and four with the homozygous c.521CC genotype ingested a single 4-mg dose of rosiglitazone and a single 15-mg dose of pioglitazone in a cross-over study with a wash-out period of at least 1 week.

RESULTS

SLCO1B1 polymorphism had no statistically significant effect on any of the pharmacokinetic variables of rosiglitazone, pioglitazone or their metabolites. The mean ± SD area under the plasma rosiglitazone concentration–time curve from time 0 to infinity (AUC_0–∞) was 2024 ± 561 ng ml⁻¹ h in the c.521TT subjects, 1763 ± 288 ng ml⁻¹ h in the c.521TC subjects (geometric mean ratio c.521TC/c.521TT 0.89; 95% confidence interval 0.72, 1.11) and 1729 ± 346 ng ml⁻¹ h in the c.521CC subjects (c.521CC/c.521TT 0.87; 0.63, 1.20). The AUC_0–∞ of pioglitazone averaged 6244 ± 1909 ng ml⁻¹ h in the c.521TT subjects, 5123 ± 1165 ng ml⁻¹ h in the c.521TC subjects (c.521TC/c.521TT 0.83; 0.65, 1.06) and 4851 ± 1123 ng ml⁻¹ h in the c.521CC subjects (c.521CC/c.521TT 0.79; 0.55, 1.14). There was a significant correlation between the AUC_0–∞ of rosiglitazone and pioglitazone (r = 0.717, P < 0.001).

CONCLUSIONS

The SLCO1B1 c.521T→C SNP does not affect the pharmacokinetics of rosiglitazone or pioglitazone, indicating that OATP1B1 plays no significant role in the disposition of these drugs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• A common single nucleotide polymorphism (SNP) (c.521T→C) of the SLCO1B1 gene, encoding the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1, has been associated with marked changes in the pharmacokinetics of the antidiabetic drug repaglinide.
• Rosiglitazone and pioglitazone are competitive inhibitors of OATP1B1 and might thus be its substrates.
• Gemfibrozil, an inhibitor of OATP1B1 in vitro, considerably increases the plasma concentrations of rosiglitazone and pioglitazone in vivo in humans.

WHAT THIS STUDY ADDS

• The SLCO1B1 c.521T→C SNP was not associated with changes in rosiglitazone or pioglitazone pharmacokinetics in healthy volunteers.
• OATP1B1 is thus unlikely to play an important role in the disposition of rosiglitazone or pioglitazone.

     

Paediatric drug development: are population models predictive of pharmacokinetics across paediatric populations?

AIMS

To assess the predictive value of a model-based approach for dose selection across paediatric populations in early clinical drug development.

METHODS

Abacavir was selected as a paradigm compound using data across a wide age range. Abacavir pharmacokinetics (PK) in children were analysed separately from infants and toddlers. Two independent models were obtained, and systemic exposure (AUC) was then simulated across populations based on the estimates from each model. Drug exposures in infants and toddlers were predicted using pharmacokinetic parameter distributions obtained from children, and the other way around.

RESULTS

The pharmacokinetic models (a two-compartment PK model for infants and toddlers and a one compartment PK model for children) accurately described the exposure in the population from which they were built. However, neither model predicted exposure in a different population: in infants, the median AUC (95%^-CI) was estimated at 7.03 (6.72, 7.48) µg ml⁻¹ h, whilst it was predicted at 5.75 (4.82, 6.26) µg ml⁻¹ h; in children, the estimated median AUC was 6.96 (5.85, 7.91) µg ml⁻¹ h, whilst the predicted value was 6.45 (5.80, 7.01) µg ml⁻¹ h.

CONCLUSIONS

These findings suggest that the assumption of an identical (linear or nonlinear) correlation between pharmacokinetic parameters and demographic factors may not hold true across age groups. Whilst the use of modelling enables accurate characterization of pharmacokinetic properties, extrapolations based on such parameter estimates may have limited value due to differences in the impact of developmental growth across populations.     

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.

     

Pharmacokinetics of lamivudine in subjects receiving peritoneal dialysis in end-stage renal failure

What is already known about this subject

• Prior to the conduct of this study, information on the pharmacokinetics of lamivudine in subjects with renal impairment was limited to patients on haemodialysis. (Br J Clin Pharmacol 1998; 46: 21–7).
• No pharmacokinetic data were available on subjects receiving lamivudine who were concurrently receiving peritoneal dialysis.
• With increasing numbers of individuals opting for peritoneal dialysis, the need to establish if dose modification was necessary in this setting was important to ensure efficacious and safe drug exposures were being obtained.

What this study adds

• This study demonstrated that similar to patients receiving haemodialysis, dose modifications based on reductions in renal function (i.e. decreased CL_CR), also applied to subjects on peritoneal dialysis.

Aims

To establish whether peritoneal dialysis (PD) requires dosing modification from the CL_CR-corrected lamivudine dose in end-stage renal failure subjects.

Methods

This was an open-label cohort study. A total of 12 subjects undergoing PD, six continuous ambulatory peritoneal dialysis (CAPD) and six automated peritoneal dialysis (APD), for at least 3 months received lamivudine 10 mg (5 mg ml ⁻¹ × 2 ml) daily for 8 consecutive days, followed by an intensive pharmacokinetic assessment. Urine and dialysate were collected from 0 to 24 h postdose on day 8 where possible. Pharmacokinetic parameters were calculated using noncompartmental techniques.

Results

The plasma pharmacokinetic results demonstrated that peritoneal dialysis clearance (CL_D) of lamivudine was similar between APD and CAPD patients with median (range) of 0.19 l h⁻¹ (0.14–0.25) and 0.1 l h⁻¹ (0.09–0.25), respectively. CL_D was approximately 1/15th to 1/30th of plasma clearance, demonstrating that peritoneal dialysis does not contribute significantly to overall lamivudine clearance in this patient population. The AUC(0,24 h) of lamivudine given 10 mg daily to APD and CAPD patients was 3430 ng ml⁻¹ h and 3469 ng ml⁻¹ h, respectively, similar to historical data obtained in patients with normal renal function administered at the normal dose of 100 mg daily (3781 ng ml⁻¹ h). There were no clinically significant changes in any safety assessments that were attributable to lamivudine.

Conclusions

ESRD patients who receive CAPD or APD require no supplemental dosing. These patients should follow the standard dosing reduction for patients infected with HIV or HBV with renal dysfunction.     

The ability of atropine to prevent and reverse the negative chronotropic effect of fingolimod in healthy subjects

WHAT IS KNOWN ABOUT THIS SUBJECT

• Clinical pharmacology and clinical therapeutic studies of fingolimod demonstrate that heart rate after the initial dose decreases by about 10–20% while normal circadian rhythm is preserved. With continued daily dosing, heart rate returns to normal over the next 2 weeks.
• This negative chronotropic effect is consistent with the binding of fingolimod-phosphate to the sphingosine-1-phosphate receptor on atrial myocytes.

WHAT THIS STUDY ADDS

• The present clinical pharmacology study demonstrates that atropine administered at usual therapeutic doses can prevent the decrease in heart rate when given concomitantly with fingolimod and can counteract the decrease in heart rate when give at the time of the typical heart rate nadir, 4 h after the fingolimod dose.
• Although therapeutic intervention is rarely needed for reduced heart rate in patients receiving fingolimod, atropine is an option, should this be desired.

AIMS

The authors determined whether intravenous atropine can prevent or counteract the negative chronotropic effect of the immunomodulator fingolimod.

METHODS

In this randomized, placebo-controlled, two-period, crossover study, 12 healthy subjects received 5 mg fingolimod orally concurrently with intravenous atropine (titrated to a heart rate of 110–120 beats min⁻¹) or intravenous placebo. A second group of 12 subjects received atropine/placebo 4 h after the fingolimod dose. Continuous telemetry measurements were made for 24 h after each fingolimod dose.

RESULTS

Fingolimod administration alone yielded a heart rate nadir of 51 ± 5 beats min⁻¹ at a median 4 h postdose with heart rate remaining depressed at 51–64 beats min⁻¹ over the rest of the day. Concurrent administration of fingolimod and atropine yielded a nadir of 66 ± 6 beats min⁻¹ resulting in an atropine : placebo ratio (90% confidence interval) of 1.30 (1.22, 1.36). When atropine was administered at the time of the nadir, it was able to reverse the negative chronotropic effect of fingolimod from a heart rate of 56 ± 9 beats min⁻¹ (placebo) to 64 ± 8 beats min⁻¹ (atropine) resulting in an atropine : placebo ratio of 1.15 (1.04, 1.26). Atropine had no influence on the pharmacokinetics of fingolimod.

CONCLUSIONS

Atropine administered concurrently with fingolimod prevented the heart rate nadir that typically occurs 4 h postdose. Atropine administered at the time of the heart rate nadir was able to reverse the negative chronotropic effect of fingolimod.