Oral diacetylmorphine (heroin) yields greater morphine bioavailability than oral morphine: bioavailability related to dosage and prior opioid exposure

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Venosclerosis prevents many opioid addicts in heroin substitution programmes from injecting intravenously, which makes consideration of other routes of administration necessary.
• Even high doses of oral diacetylmorphine are completely converted to morphine presystemically.
• Morphine bioavailability in heroin addicts after high-dose oral diacetylmorphine administration is considerably higher than expected based on prior data obtained with relatively low oral diacetylmorphine or morphine doses in healthy subjects or patients receiving treatment for pain (64–72% vs. 20–25%).

WHAT THIS STUDY ADDS

• Morphine influx into systemic circulation is more rapid after oral diacetylmorphine than after oral morphine, resulting in earlier and more than double maximal concentrations.
• In opioid-dependent people, bioavailability of morphine from oral doses of diacetylmorphine is also 37% higher than that of oral morphine.
• Morphine bioavailability is two and 1.5 times higher in chronic users than in opioid-naive subjects after low oral doses of diacetylmorphine or morphine, respectively.
• Oral absorption of morphine from diacetylmorphine is dose dependent, i.e. bioavailability increases with diacetylmorphine dose.

AIMS

In the Swiss heroin substitution trials, patients are treated with self-administered diacetylmorphine (heroin). Intravenous administration is not possible in patients that have venosclerosis. Earlier studies have demonstrated that oral diacetylmorphine may be used, although it is completely converted to morphine presystemically. Morphine bioavailability after high-dose oral diacetylmorphine is considerably higher than would be predicted from low-dose trials. The aim was to investigate whether the unexpectedly high bioavailability is due to a difference in the drug examined, and whether it depends on previous exposure or on dose.

METHODS

Opioid-naive healthy volunteers and dependent patients from the Swiss heroin trials (n = 8 per group) received low doses of intravenous and oral deuterium-labelled morphine and diacetylmorphine, respectively. Patients also received a high oral diacetylmorphine dose.

RESULTS

The maximum plasma concentration (C_max) of morphine was twofold higher after oral diacetylmorphine than after morphine administration in both groups. However, morphine bioavailability was considerably higher in chronic users [diacetylmorphine 45.6% (95% confidence interval 40.0, 51.3), morphine 37.2% (30.1, 44.3)] than in naive subjects [diacetylmorphine 22.9% (16.4, 29.4), morphine 23.9% (16.5, 31.2)] after low oral doses (48.5 µmol) of either diacetylmorphine or morphine. Morphine clearance was similar in both groups. Moreover, oral absorption of morphine from diacetylmorphine was found to be dose dependent, with bioavailability reaching 64.2% (55.3, 73.1) for high diacetylmorphine doses (1601 µmol).

CONCLUSIONS

Oral absorption of opioids is substance-, dose- and patient collective-dependent, suggesting that there may be a saturation of first-pass processes, the exact mechanism of which is not yet understood.     

Sublingual administration of furosemide: new application of an old drug

What is already known about this subject

• Furosemide is an effective diuretic, but its absorption may be too slow to allow oral treatment in certain patients.

What this study adds

• In healthy volunteers, sublingual administration is associated with a higher C_max, a higher bioavailability and a more accentuated initial natriuretic response than oral furosemide. Sublingual administration may offer advantages over oral administration of furosemide in certain clinical situations.

Background

In patients with decompensated heart failure, absorption of orally administered furosemide may be delayed, possibly leading to impaired pharmacodynamic effects. Sublingual administration may represent an alternative in such situations.

Methods

In a crossover study including 11 healthy men, 20 mg furosemide was administered intravenously, orally and sublingually on three different days. Pharmacokinetics and pharmacodynamics were assessed from repeated blood and urine samples.

Results

Compared with oral administration, sublingual administration was associated with 43% higher C_max[difference 215 ng ml⁻¹, 95% confidence interval (CI) 37, 392], a higher urinary recovery (8.9 vs. 7.3 mg, difference 1.6 mg, 95% CI 0.3, 2.9), an 28% higher AUC (difference 328 ng h⁻¹ ml⁻¹, 95% CI 24, 632) and a higher bioavailability of furosemide (59 vs. 47%, difference 12.0%, 95% CI −1.2, 25.2). Sodium excretion was higher after sublingual compared with oral administration (peak excretion rate 1.8 vs. 1.4 mmol min⁻¹, P < 0.05), whereas urine volume did not differ significantly between the two application modes. In comparison, intravenous administration showed the expected more rapid and intense response.

Conclusion

Sublingually administered furosemide tablets differ in certain kinetic and dynamic properties from identical tablets given orally. Sublingual administration of furosemide may offer therapeutic advantages in certain groups of patients.     

Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects

AIM

Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of ¹⁴C-vismodegib with single and multiple oral doses.

METHODS

Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a ¹⁴C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for ¹⁴C-vismodegib by accelerator mass spectrometry.

RESULTS

Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h⁻¹, 16.4 l and 31.8%, respectively. Parallel concentration–time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h⁻¹ and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing.

CONCLUSION

Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.     

Simultaneous oral therapeutic and intravenous 14C‐microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin

Aim

To determine the absolute oral bioavailability (F_p.o.) of saxagliptin and dapagliflozin using simultaneous intravenous ¹⁴C‐microdose/therapeutic oral dosing (i.v.micro + oraltherap).

Methods

The F_p.o. values of saxagliptin and dapagliflozin were determined in healthy subjects (n = 7 and 8, respectively) following the concomitant administration of single i.v. micro doses with unlabelled oraltherap doses. Accelerator mass spectrometry and liquid chromatography‐tandem mass spectrometry were used to quantify the labelled and unlabelled drug, respectively.

Results

The geometric mean point estimates (90% confidence interval) F_p.o. values for saxagliptin and dapagliflozin were 50% (48, 53%) and 78% (73, 83%), respectively. The i.v.micro had similar pharmacokinetics to oraltherap.

Conclusions

Simultaneous i.v.micro + oraltherap dosing is a valuable tool to assess human absolute bioavailability.     

The concentration of oxazepam and oxazepam glucuronide in oral fluid, blood and serum after controlled administration of 15 and 30 mg oxazepam

AIMS

To measure and compare the concentration–time profiles of oxazepam and oxazepam glucuronide in blood, serum and oral fluid within the scope of roadside testing.

METHODS

Biological samples were collected from eight male subjects after ingestion of 15 or 30 mg oxazepam on separate dosing occasions with an interval of 7 days. The concentration–time profiles of oxazepam and oxazepam glucuronide were fitted by using a one-compartment model.

RESULTS

For oxazepam and oxazepam glucuronide, the mean oral fluid/blood ratios were 0.05 (range 0.04–0.07) and 0.004 (range 0.002–0.006), respectively. The concentration–time profiles in oral fluid paralleled those in blood.

CONCLUSION

After oral administration of therapeutic doses of oxazepam, concentrations in oral fluid are very much lower than those in blood, and those of oxazepam glucuronide are much lower than those of the parent compound. Nevertheless, assay of oral fluid for oxazepam can be used to detect recent ingestion of the drug in drivers suspected of impaired driving performance.

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT

• Concentration–time profiles of drugs in oral fluid generally run parallel to those in blood.
• In general, oral fluid contains more parent drug than metabolites.
• For some benzodiazepines it has been shown that concentrations are lower in oral fluid than in blood.

WHAT THIS STUDY ADDS

• The concentration–time profile of oxazepam in oral fluid after a single dose of oxazepam runs parallel to blood and is dose dependent.
• Concentration ratios (oral fluid/blood and oral fluid/serum) of oxazepam and oxazepam glucuronide after controlled intake of a single dose of oxazepam are presented.

     

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.

     

Developmental pharmacokinetics of ciclosporin--a population pharmacokinetic study in paediatric renal transplant candidates

What is already known about this subject

• Ciclosporin is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics.
• It is likely that the inter- and intraindividual variability in ciclosporin pharmacokinetics and dose requirements is even larger in children than in adults as a result of variation in biological maturation status.
• However, data on the developmental pharmacokinetics of ciclosporin, as well as other CYP3A4 substrate drugs, in children are scarce.

What this study adds

• Adult CYP3A4 activity seems to be reached by the age of 6–12 months, and allometrically scaled body weight is a good predictor of the hepatic clearance of ciclosporin, a CYP3A4 substrate.
• Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age.
• These conclusions were reached using a robust modelling approach (NONMEM) with rich paediatric pharmacokinetic data collected after full i.v. and p.o. profiles.

Aims

To use population pharmacokinetic modelling to characterize the influence of developmental and demographic factors on the pharmacokinetic variability of ciclosporin.

Methods

Pharmacokinetic modelling was performed in NONMEM using a dataset comprising 162 pretransplant children, aged 0.36–17.5 years. Ciclosporin was given intravenously (3 mg kg⁻¹) and orally (10 mg kg⁻¹) on separate occasions followed by blood sampling for 24 h.

Results

A three-compartment model with first-order absorption without lag-time best described the pharmacokinetics of ciclosporin. The most important covariate affecting systemic clearance (CL) and distribution volume (V) was body weight (BW; scaled allometrically), responsible for a fourfold difference in uncorrected ciclosporin CL and a sixfold difference in ciclosporin V. The other significant covariates, haematocrit, plasma cholesterol and creatinine, were estimated to explain 20–30% of interindividual differences in CL and V of ciclosporin. No age-related changes in oral bioavailability or in BW-normalized V were seen. The BW-normalized CL (CL/BW) declined with age and prepubertal children (<8 years) had an approximately 25% higher CL/BW than did older children. Normalization of CL for allometric BW (BW^3/4) removed its relationship to age.

Conclusion

The relationship between CL and allometric BW is consistent with a gradual reduction in relative liver size, until adult values, and a relatively constant CYP3A4 content in the liver from about 6–12 months of age to adulthood. Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age. These findings can enable better individualization of ciclosporin dosing in infants, children and adolescents.     

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.     

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.     

The absolute bioavailability of racemic ketamine from a novel sublingual formulation

Aim

The principal study objective was to investigate the pharmacokinetic characteristics of a new sublingual ketamine wafer and to establish its absolute bioavailability and local tolerability.

Methods

The study was of open label, two way randomized crossover design in eight healthy male volunteers. Each participant received either a single 10 mg intravenous dose as a constant rate 30 min infusion or a 25 mg sublingual dose of ketamine wafer in two treatment periods with a 7 day wash out. Pharmacokinetic blood sampling and local tolerability and safety assessments were carried out during 24 h following both dosing occasions. Plasma concentrations were analyzed by non-compartmental methods and local tolerability was assessed using modified Likert scales.

Results

The median (90% CI lower, upper limit) absolute bioavailability of sublingual ketamine was 29% (27, 31%). The first quantifiable plasma ketamine concentration was observed within 5 min for all eight participants for both routes of administration and the median (min–max) time of the peak plasma concentration was 0.75 h (0.25–1.0 h) after sublingual administration. The ketamine wafer had very good local tolerability.

Conclusion

Sublingual administration of the ketamine wafer resulted in rapid absorption. The ketamine wafer has comparable bioavailability with other oral transmucosal formulations of ketamine but with markedly reduced inter-subject variability, warranting further evaluation as an analgesic adjunct.     

Acute passive cigarette smoke exposure and inhaled human insulin (Exubera) pharmacokinetics

AIMS

Relative to nonsmokers, the bioavailability of inhaled human insulin (Exubera®; EXU) is markedly increased in chronic smokers. The pharmacokinetics of EXU following passive cigarette smoke exposure is unknown.

METHODS

In an open-label, crossover study, healthy nonsmoking volunteers received two treatments in randomized sequence separated by a 2-week wash-out: (i) EXU 3 mg with no passive smoke exposure and (ii) EXU 3 mg after passive smoke exposure (atmospheric nicotine levels 75–125 μg m⁻³) for 2 h. Blood samples were obtained at prespecified times up to 6 h after EXU administration.

RESULTS

Twenty-seven subjects completed both study periods. Mean plasma insulin AUC₀₋₃₆₀ decreased by 17% [ratio 83%, 95% confidence interval (CI) 68.8, 99.5] and mean C_max by 29% (ratio 71%, 95% CI 59.8, 83.1) after passive cigarette smoke exposure. The median (range) t_max was 60 min (20–120 min) and 75 min (20–360 min) in the EXU with no exposure and EXU passive exposure groups, respectively. EXU was well tolerated.

CONCLUSIONS

Unlike active chronic smoking, acute passive cigarette smoke exposure modestly decreases EXU bioavailability and thus should not increase hypoglycaemia risk. These results are consistent with those from published literature involving technetium-labelled diethylenetriamine penta-acetic acid and suggest that passive cigarette smoke exposure causes an acute decrease in lung permeability vs. active smoking, which causes an increase in permeability.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Active cigarette smoking is associated with increased permeability of the pulmonary alveolar epithelium, resulting in faster absorption of inhaled drugs such as Exubera® (EXU). Absorption of EXU is increased approximately twice to four times as much in chronic smokers compared with nonsmokers.
• The rate of clearance of radioaerosols such as technetium-labelled diethylenetriamine penta-acetic acid is decreased in response to passive smoke exposure.

WHAT THIS STUDY ADDS

• Passive smoke exposure causes a decrease in lung permeability, an effect opposite to that of active smoking.
• Acute passive smoke exposure results in a decrease in EXU bioavailability and does not create a risk of hypoglycaemia.
• These results are consistent with previous studies of radioaerosol lung clearance.

     

Clindamycin and taste disorders

What is already known about this subject.

• The antibiotic clindamycin has a bitter taste when it is used orally.

What this study adds

• A case series on oral as well as i.v. use of clindamycin associated with taste disorders is presented.
• After corrections in a case-by-case analysis for several possible confounders such as indication, clindamycin is disproportionally associated with taste disorders.
• Serum and hence saliva and sputum clindamycin levels seem to be responsible for this reversible adverse drug reaction.

Aims

Topical use of clindamycin has been associated with taste disorders in the literature, but little is known about the nature of this adverse drug reaction. The aim of this article was to describe reports of clindamycin-induced taste disorders and to analyse the factors involved.

Methods

The adverse drug reaction database of the Netherlands Pharmacovigilance Centre was searched for reports concerning taste disorders with antibiotics. Clinical review of the cases and statistical analysis with logistic regression were performed. Characteristics of patients who reported taste disorders were compared for age, gender and formulation in clindamycin vs. other antibiotic users.

Results

Taste disorders were reported in seven (18%) of the clindamycin cases. In five reports an oral formulation was involved, in one report intravenous (i.v.) administration and in one report both formulations were used. Latency was <1 day after start and in one case taste disorders were present repeatedly at 10 min after every i.v. application. The adjusted reporting odds ratio was 7.0 (95% confidence interval 2.8, 17.3) and supports a possible causal relationship.

Conclusions

The association of clindamycin and taste disorders is supported by disproportionality analysis and seems to be independent of possible confounders such as age, gender and infections. The case reports suggest a role for clindamycin concentrations excreted in body fluids like saliva.     

Enhancement of oral bioavailability of the poorly water-soluble drug silybin by sodium cholate/ phospholipid-mixed micelles

Aim:

To evaluate a mixed micellar drug delivery system composed of sodium cholate and phospholipid for oral administration of silybin, a promising hepatoprotectants.

Methods:

The optimum formulation of sodium cholate/phospholipid-mixed micelles containing silybin was obtained based on the study of pseudo-ternary phase diagram. The dissolution of silybin-mixed micelles was investigated. The pharmacokinetic characteristics and bioavailability after oral administration of silybin-mixed micelles and silybin-N-methylglucamine were compared in dogs.

Results:

The mean particle size of prepared mixed micelles was 75.9±4.2 nm. The largest solubility of silybin was found to be 10.0±1.1 mg/mL in the optimum formulation of mixed micelles. The silybin-sodium cholate/phospholipid-mixed micelles showed a very slow release of silybin 17.5% (w/w) within 72 h in phosphate buffer (pH 7.4) and 15.6% (w/w) in HCl solution (pH 1.2). After oral administration to dogs, the relative bioavailability of mixed micelles versus silybin-N-methylglucamine in dogs was 252.0%.

Conclusion:

Sodium cholate/phospholipid-mixed micelles are promising carriers in orally delivery of silybin, considering their capability of enhancing bioavailability and large-scale production.     

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 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

     

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.

     

Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects

AIM

To determine if reported lower plasma concentrations of artemisinin derivatives for malaria in pregnancy result from reduced oral bioavailability, expanded volume of distribution or increased clearance.

METHODS

In a sequentially assigned crossover treatment study, pregnant women with uncomplicated falciparum malaria received i.v. artesunate (i.v. ARS) (4 mg kg⁻¹) on the first day and oral ARS (4 mg kg⁻¹) on the second, or, oral on the first and i.v. on the second, in both groups followed by oral ARS (4 mg kg⁻¹ day⁻¹) for 5 days. Plasma concentrations of ARS and dihyroartemisinin (DHA) were measured by liquid chromatography-mass-spectrometry on days 0, 1, 2 and 6. Controls were the same women restudied when healthy (3 months post partum).

RESULTS

I.v. ARS administration resulted in similar ARS and DHA pharmacokinetics in pregnant women with malaria (n = 20) and in controls (n = 14). Oral administration resulted in higher total drug exposure in pregnancy [AUC (95% CI) in (ng ml⁻¹ h)/(mg kg⁻¹)] of 55.1 (30.1, 100.0) vs. 26.5 (12.2, 54.3) for ARS, P = 0.002 and 673 (386, 1130) vs. 523 (351, 724) for DHA, P = 0.007. The corresponding median absolute oral bioavailability (F%) was 21.7 (12.6, 75.1) vs. 9.9 (6.0, 36.81) for ARS (P = 0.046) and 77.0 (42.2, 129) vs. 72.7 (42.0, 87.7) for DHA, P = 0.033. Total DHA exposure was lower at day 6 in pregnant women with malaria (P < 0.001) compared with day 0 or 1, but not in the controls (P = 0.084).

CONCLUSIONS

This study demonstrates the effects of malaria on oral ARS drug disposition are greater than those of pregnancy. This probably results from a disease related reduction in first pass metabolism. The data are reassuring regarding current dosing recommendations.     

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.

     

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.     

Influence of food intake on the bioavailability and efficacy of oral calcitonin

AIMS

To investigate the influence of food intake on the bioavailability and pharmacodynamic effects of salmon calcitonin (sCT).

METHODS

A single-blind, randomized, partly placebo-controlled study was conducted in 36 healthy postmenopausal female volunteers aged 62–74 years. The influence of food intake on oral dosing with 0.8 mg of sCT at 22.00 h was evaluated for a (i) predose meal at 18.00 h, (ii) predose meal at 20.00 h, (iii) predose meal at 21.00 h, (iv) postdose meal at 22.10 h, (v) no meal, and (vi) meal at 20.00 h and placebo at 22.00 h. Study biomarkers were plasma sCT levels and changes in the bone resorption marker CTX-I (C-terminal telopeptide of collagen type I).

RESULTS

The predose meal at 18.00 and 21.00 h significantly decreased relative oral bioavailability of sCT to 26% [95% confidence interval (CI) 0.09, 0.73 and 0.09, 0.75, P= 0.009 and P= 0.01]. The meal consumed 10 min after dosing decreased the oral bioavailability of sCT to 59% (95% CI 0.21, 1.68), although nonsignificant (P= 0.48). This decreased bioavailability led to lower relative suppression of serum CTX-I, with an AUC of the 4-h efficacy response of −91%–×–hours for those receiving a meal at 18.00 h, compared with −238%–×–hours for fasting subjects. The Dunnett-adjusted difference between these two treatment sequences was 147%–×–hours (95% CI 68, 225) (P= 0.0003). The AUC was comparable among fasting subjects and those consuming a meal 10 min after dosing.

CONCLUSIONS

Postprandial dosing may limit the bioavailability of orally administered sCT. Maximal benefit can be achieved by dosing at least 10 min prior to meal time.