Systemic exposure of topical erythromycin in comparison to oral administration and the effect on cytochrome P450 3A4 activity

Aims

Erythromycin is a macrolide antibiotic, which is frequently used as a topical formulation for the treatment of acne. It is also known as an inhibitor of the cytochrome P450 (CYP) isoenzyme 3A4. In this study, the systemic availability of topical erythromycin, hence the influence on the activity of CYP3A, is evaluated in comparison to orally administered erythromycin.

Methods

Sixteen healthy volunteers received consecutively topical (two applications of 800 mg) and oral erythromycin (two dose groups, 250 and 1000 mg, with n = 8) to assess erythromycin pharmacokinetics. A microdose of midazolam (3 μg orally) was used to determine the effect on CYP3A activity.

Results

After topical administration, erythromycin was detected in the plasma of every participant without causing a statistically significant alteration of CYP3A activity. After oral administration, the dose-normalized erythromycin exposure (AUC_∞) was 1335 h ng ml⁻¹ after 250 mg and 3-fold higher after the 1000 mg dose (4051 h ng ml⁻¹; P < 0.01), suggesting nonlinear pharmacokinetics of erythromycin. Both oral doses inhibited CYP3A activity; midazolam clearance was decreased to 61% (250 mg) and 21% (1000 mg). The relationship between erythromycin exposure and CYP3A activity (Hill equation) revealed a 50% reduction of CYP3A activity by an erythromycin AUC_∞ of 2106 h ng ml⁻¹.

Conclusions

Topical erythromycin did not cause clinically relevant CYP3A alterations, although low systemic availability of erythromycin was observed. This supports the assumption that treatment with topical erythromycin is not critical in terms of CYP3A inhibition. Furthermore, substantial nonlinearity of erythromycin pharmacokinetics after two different oral doses was observed, possibly due to autoinhibition.     

The impact of co-administration of ketoconazole and rifampicin on the pharmacokinetics of apremilast in healthy volunteers

AimsTwo clinical studies were conducted to determine possible drug−drug interactions between apremilast and a strong CYP3A4 inhibitor, ketoconazole, or a potent CYP3A4 inducer, rifampicin. The main objectives of these two studies were to evaluate the impact of multiple doses of ketoconazole on the pharmacokinetics of apremilast and its metabolites, and the effect of multiple oral doses of rifampicin on the pharmacokinetics of apremilast.MethodsThese single centre, open label, sequential treatment studies in healthy subjects included two treatment periods for ketoconazole and three treatment periods for rifampicin. Apremilast was administered as a 20 mg (ketoconazole study) or 30 mg (rifampicin study) single oral dose.ResultsKetoconazole increases overall exposure (AUC(0,∞)) of apremilast by ≈36% (2827 vs. 2072 ng ml⁻¹ h, 90% CI = 126.2, 147.5) and peak exposure (C_max) by 5% (247 vs. 236 ng ml⁻¹). Multiple doses of rifampicin increase apremilast clearance ≈3.6-fold and decrease apremilast mean AUC(0,∞) by ≈72% (3120 vs. 869 ng ml⁻¹ h, 90% CI = 25.7, 30.4) and C_max (from 290 vs. 166 ng ml⁻¹) relative to that of apremilast given alone. A 30 min intravenous infusion of rifampicin 600 mg had negligible effects on the overall exposure (AUC(0,∞)) of apremilast (2980 vs. 3120 ng ml⁻¹ h, 90% CI = 88.0, 104.1).ConclusionKetoconazole slightly decreased apremilast clearance, resulting in a small increase in AUC which is probably not meaningful clinically. However, the effect of CYP3A4 induction by rifampicin on apremilast clearance is much more pronounced than that of CYP3A4 inhibition by ketoconazole. Strong CYP3A4 inducers may result in a loss of efficacy of apremilast because of decreased drug exposure.     

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.

     

Flurbiprofen concentration in soft tissues is higher after topical application than after oral administration

Aim

To compare tissue concentrations of flurbiprofen resulting from topical application and oral administration according to the regulatory approved dosing guidelines.

Method

Sixteen patients were included in this study. Each patient was randomly assigned to the topical application or oral administration group. In each group, a pair of tapes or a tablet, containing a total of 40 mg flurbiprofen, was administered twice at 16 and 2 h before the surgery.

Results

The flurbiprofen concentration in the fat, tendon, muscle and periosteum tissues was significantly higher (P < 0.0330) after topical application (992 ng g⁻¹ [95% CI 482, 1503], 944 [95% CI 481, 1407], 492 [95% CI 248, 735], and 455 [95% CI 153, 756], respectively) than after oral administration (150 ng g⁻¹ [95% CI 84, 217], 186 [95% CI 118, 254], 82 [95% CI 49, 116],and 221 [95% CI, 135, 307], respectively).

Conclusion

Topical application is an effective method to deliver flurbiprofen to the human body, particularly to soft tissues near the body surface.     

An effect of moderate hepatic impairment on the pharmacokinetics and safety of darapladib

Aim/MethodsThis was a phase 1, open label, non-randomized study designed to assess the pharmacokinetics and safety/tolerability of 10 consecutive once daily 40 mg oral doses of darapladib in subjects with moderate hepatic impairment (n = 12) compared with matched healthy volunteers (n = 12).ResultsFor total darapladib, a small increase in total and peak exposure was observed in the subjects with moderate hepatic impairment compared with the subjects with normal hepatic function. The area under the plasma concentration−time curve during a dosing interval of duration τ (AUC(0,τ), geometric mean 223 ng ml⁻¹ h [90% CI 158, 316 ng ml⁻¹h], in moderate hepatic impaired subjects, vs. geometric mean 186 ng ml⁻¹h [90% CI 159, 217 ng ml⁻¹h], in healthy subjects) and maximum concentration (C_max) were 20% and 7% higher, respectively, in the subjects with moderate hepatic impairment than in the healthy control subjects and there was no change in time to maximum concentration (t_max). Protein binding was performed to measure the amount of unbound drug vs. bound. Steady-state was achieved by day 10 for darapladib and its metabolites (M4, M3 and M10). Darapladib was generally well tolerated, with adverse events (AEs) reported by seven subjects in the hepatic impairment group and three subjects in the healthy matched group (five and one of which were drug-related AEs, respectively). The most common AEs were gastrointestinal. These AEs were mostly mild to moderate and there were no deaths, serious AEs or withdrawals due to AEs.ConclusionsThe results of this phase 1 study show that darapladib (40 mg) is well tolerated and its pharmacokinetics remain relatively unchanged in patients with moderate hepatic impairment.     

The efficacy of parecoxib on systemic inflammatory response associated with cardiopulmonary bypass during cardiac surgery

Aims

Cardiopulmonary bypass (CPB) during cardiac surgery is well known to be associated with the development of a systemic inflammatory response. The efficacy of parecoxib in attenuating this systemic inflammatory response is still unknown.

Methods

Patients undergoing elective mitral valve replacement with CPB were assessed, enrolled and randomly allocated to receive parecoxib (80 mg) or placebo. Blood samples were collected in EDTA vials for measuring serum cytokine concentrations, troponin T, creatinekinase myocardial‐brain isoenzyme CK‐MB concentrations and white cell counts.

Results

Compared with the control group, IL‐6 and IL‐8‐values in the parecoxib group increased to a lesser extent, peaking at 2 h after the end of CPB (IL‐6 31.8 pg ml⁻¹ ± 4.7 vs. 77.0 pg ml⁻¹ ± 14.1, 95% CI −47.6, −42.8, P < 0.001; IL‐8 53.6 pg ml⁻¹ ± 12.6 vs. 105.7 pg ml⁻¹ ± 10.8, 95% CI −54.8, −49.4, P < 0.001). Peak concentrations of anti‐inflammatory cytokine IL‐10 occurred immediately after termination of CPB and were higher in the parecoxib group (115.7 pg ml⁻¹ ± 10.5 vs. 88.4 pg ml⁻¹ ± 12.3, 95% CI 24.7, 29.9, P < 0.001). Furthermore, the increase in neutrophil counts caused by CPB during cardiac surgery was inhibited by parecoxib. The increases in serum troponin T and CK‐MB concentrations were also significantly attenuated by parecoxib in the early post‐operative days. Peak serum concentrations of CK‐MB in both groups occurred at 24 h post‐CPB (17.4 μg l⁻¹ ± 5.2 vs. 26.9 μg l⁻¹ ± 6.9, 95% CI −10.9, −8.1, P < 0.001). Peak troponin T concentrations occurred at 6 h post‐bypass (2 μg l⁻¹ ± 0.62 vs. 3.5 μg l⁻¹ ± 0.78, 95% CI −1.7, −1.3, P < 0.001).

Conclusion

Intra‐operative parecoxib attenuated the systemic inflammatory response associated with CPB during cardiac surgery and lowered the biochemical markers of myocardial injury.     

Evaluation of effect of impaired renal function on lamivudine pharmacokinetics

Aims

This study aimed to describe lamivudine pharmacokinetics in patients with impaired renal function and to evaluate the consistency of current dosing recommendations.

Methods

A total of 244 patients, ranging in age from 18 to 79 years (median 40 years) and in bodyweight from 38 to 117 kg (median 71 kg), with 344 lamivudine plasma concentrations, were analysed using a population pharmacokinetic analysis. Serum creatinine clearance (CLCR) was calculated using the Cockcroft–Gault formula; 177 patients had normal renal function (CLCR > 90 ml min⁻¹), 50 patients had mild renal impairment (CLCR = 60–90 ml min⁻¹), 20 patients had moderate renal impairment (CLCR = 30–60 ml min⁻¹), and five patients had severe renal impairment (CLCR < 30 ml min⁻¹).

Results

A two-compartment model adequately described the data. Typical population estimates (percentage interindividual variability) of the apparent clearance (CL/F), central (V_c/F) and peripheral volumes of distribution (V_p/F), intercompartmental clearance (Q/F) and absorption rate constant (K_a) were 29.7 l h⁻¹ (32%), 68.2 l, 114 l, 10.1 l h⁻¹ (85%) and 1 h⁻¹, respectively. Clearance increased significantly and gradually with CLCR. Our simulations showed that a dose of 300 mg day⁻¹ in patients with mild renal impairment could overexpose them. A dose of 200 mg day⁻¹ maintained an exposure close to that of adults with normal renal function. However, the current US Food and Drug Administration recommendations for lamivudine in other categories of patients (from severe to moderate renal impairment) provided optimal exposures.

Conclusions

Lamivudine elimination clearance is related to renal function. To provide optimal exposure, patients with mild renal impairment should receive 200 mg day⁻¹ instead of 300 mg day⁻¹.     

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol

Aim

To study the differences in QT_c interval on ECG in response to a single oral dose of rac-sotalol in men and women.

Methods

Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration–QTc analyses were performed using a linear mixed effects model.

Results

Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QT_cI) most effectively removed the heart rate dependency of the QT_c interval. Mean QT_cI was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QT_cI in both genders. The largest mean change in QT_cI (ΔQT_cI) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean C_max 1.8 μg ml⁻¹ (range 1.1–2.8) vs. 1.4 μg ml⁻¹ (range 0.9–1.9), P = 0.0009). The slope of the concentration–ΔQT_cI relationship was steeper in women (30 ms per μg ml⁻¹ vs. 23 ms per μg ml⁻¹ in men; P = 0.0135).

Conclusions

The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.     

Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria

Aims

The aim was to investigate the QT effect of a single dose combination regimen of piperaquine phosphate (PQP) and a novel aromatic trioxolane, OZ439, for malaria treatment.

Methods

Exposure–response (ER) analysis was performed on data from a placebo-controlled, single dose, study with OZ439 and PQP. Fifty-nine healthy subjects aged 18 to 55 years received OZ439 alone or placebo in a first period, followed by OZ439 plus PQP or matching placebos in period 2. OZ439 and PQP doses ranged from 100–800 mg and 160–1440 mg, respectively. Twelve-lead ECG tracings and PK samples were collected serially pre- and post-dosing.

Results

A significant relation between plasma concentrations and placebo-corrected change from baseline QT_cF (ΔΔQT_cF) was demonstrated for piperaquine, but not for OZ439, with a mean slope of 0.047 ms per ng ml⁻¹ (90% CI 0.038, 0.057). Using an ER model that accounts for plasma concentrations of both piperaquine and OZ439, a largest mean QT_cF effect of 14 ms (90% CI 10, 18 ms) and 18 ms (90% CI 14, 22 ms) was predicted at expected plasma concentrations of a single dose 800 mg OZ439 combined with PQP 960 mg (188 ng ml⁻¹) and 1440 mg (281 ng ml⁻¹), respectively, administered in the fasted state.

Conclusions

Piperaquine prolongs the QT_c interval in a concentration-dependent way. A single dose regimen combining 800 mg OZ439 with 960 mg or 1440 mg PQP is expected to result in lower peak piperaquine plasma concentrations compared with available 3 day PQP-artemisinin combinations and can therefore be predicted to cause less QT_c prolongation.     

Determination of optimal vitamin D3 dosing regimens in HIV-infected paediatric patients using a population pharmacokinetic approach

AimsTo investigate 25-hydroxycholecalciferol [25(OH)D] population pharmacokinetics in children and adolescents, to establish factors that influence 25(OH)D pharmacokinetics and to assess different vitamin D₃ dosing schemes to reach sufficient 25(OH)D concentrations (>30 ng ml⁻¹).MethodsThis monocentric prospective study included 91 young HIV-infected patients aged 3 to 24 years. Patients received a 100 000 IU vitamin D₃ supplementation. A total of 171 25(OH)D concentrations were used to perform a population pharmacokinetic analysis.ResultsAt baseline 28% of patients had 25(OH)D concentrations below 10 ng ml⁻¹, 69% between 10 and 30 ng ml⁻¹ and 3% above 30 ng ml⁻¹. 25(OH)D pharmacokinetics were best described by a one compartment model with an additional production parameter reflecting the input from diet and sun exposure. The effects of skin phototype and bodyweight were significant on 25(OH)D production before any supplementation. The basal level was 27% lower in non-white skin phototype patients and was slightly decreased with bodyweight. No significant differences in 25(OH)D concentrations were related to antiretroviral drugs. To obtain concentrations between 30 and 80 ng ml⁻¹, patients with baseline concentrations between 10 and 30 ng ml⁻¹ should receive 100 000 IU per 3 months. However, vitamin D deficient patients (<10 ng ml⁻¹) would need an intensive phase of 100 000 IU per 2 weeks (two times) followed 2 weeks later by a maintenance phase of 100 000 IU per 3 months.ConclusionsSkin phototype and bodyweight had an influence on the basal production of 25(OH)D. According to 25(OH)D baseline concentrations, dosing schemes to reach sufficient concentrations are proposed.     

Effects of prostaglandins and nitric oxide on the renal effects of angiotensin II in the anaesthetized rat

1. The potential influences of nitric oxide (NO) and prostaglandins on the renal effects of angiotensin II (Ang II) have been investigated in the captopril-treated anaesthetized rat by examining the effect of indomethacin or the NO synthase inhibitor, N^ω-nitro-L-arginine methyl ester (L-NAME), on the renal responses obtained during infusion of Ang II directly into the renal circulation.
2. Intrarenal artery (i.r.a.) infusion of Ang II (1–30 ng kg⁻¹ min⁻¹) elicited a dose-dependent decrease in renal vascular conductance (RVC; −38±3% at 30 ng kg⁻¹ min⁻¹; P<0.01) and increase in filtration fraction (FF; +49±8%; P<0.05) in the absence of any change in carotid mean arterial blood pressure (MBP). Urine output (Uv), absolute (UNaV) and fractional sodium excretion (FENa), and glomerular filtration rate (GFR) were unchanged during infusion of Ang II 1–30 ng kg⁻¹ min⁻¹ (+6±17%, +11±17%, +22±23%, and −5±9%, respectively, at 30 ng kg⁻¹ min⁻¹). At higher doses, Ang II (100 and 300 ng kg⁻¹ min⁻¹) induced further decreases in RVC, but with associated increases in MBP, Uv and UNaV.
3. Pretreatment with indomethacin (10 mg kg⁻¹ i.v.) had no significant effect on basal renal function, or on the Ang II-induced reduction in RVC (−25±7% vs −38±3% at Ang II 30 ng kg⁻¹ min⁻¹). In the presence of indomethacin, Ang II tended to cause a dose-dependent decrease in GFR (−38±10% at 30 ng kg⁻¹ min⁻¹); however, this effect was not statistically significant (P=0.078) when evaluated over the dose range of 1–30 ng kg⁻¹ min⁻¹, and was not accompanied by any significant changes in Uv, UNaV or FENa (−21±12%, −18±16% and +36±38%, respectively).
4. Pretreatment with L-NAME (10 μg kg⁻¹ min⁻¹ i.v.) tended to reduce basal RVC (control −11.8±1.4, +L-NAME −7.9±1.8 ml min⁻¹ mmHg⁻¹×10⁻²), and significantly increased basal FF (control +15.9±0.8, +L-NAME +31.0±3.7%). In the presence of L-NAME, renal vasoconstrictor responses to Ang II were not significantly modified (−38±3% vs −35±13% at 30 ng kg⁻¹ min⁻¹), but Ang II now induced dose-dependent decreases in GFR, Uv and UNaV (−51±11%, −41±14% and −31±17%, respectively, at an infusion rate of Ang II, 30 ng kg⁻¹ min⁻¹). When evaluated over the range of 1–30 ng kg⁻¹ min⁻¹, the effect of Ang II on GFR and Uv were statistically significant (P<0.05), but on UNaV did not quite achieve statistical significance (P=0.066). However, there was no associated change in FENa observed, suggesting a non-tubular site of interaction between Ang II and NO.
5. In contrast to its effects after pretreatment with L-NAME alone, Ang II (1–30 ng kg⁻¹ min⁻¹) failed to reduce renal vascular conductance in rats pretreated with the combination of L-NAME and the selective angiotensin AT₁ receptor antagonist, {"type":"entrez-nucleotide","attrs":{"text":"GR117289","term_id":"238364164","term_text":"GR117289"}}GR117289 (1 mg kg⁻¹ i.v.). This suggests that the renal vascular effects of Ang II are mediated through AT₁ receptors. Over the same dose range, Ang II also failed to significantly reduce GFR or Uv.
6. In conclusion, the renal haemodynamic effects of Ang II in the rat kidney appear to be modulated by cyclooxygenase-derived prostaglandins and NO. The precise site(s) of such an interaction cannot be determined from the present data, but the data suggest complex interactions at the level of the glomerulus.

     

No relevant pharmacokinetic interaction between pantoprazole and mycophenolate in renal transplant patients: a randomized crossover study

Aims

Mycophenolic acid (MPA) suppresses lymphocyte proliferation through inosine monophosphate dehydrogenase (IMPDH) inhibition. Two formulations have been approved: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). Pantoprazole (PAN) inhibits gastric acid secretion, which may alter MPA exposure. Data from healthy volunteers suggest a significant drug–drug interaction (DDA) between pantoprazole and MPA. In transplant patients, a decreased MPA area under the concentration–time curve (AUC) may lead to higher IMPDH activity, which may lead to higher acute rejection risk. Therefore this DDA was evaluated in renal transplant patients under maintenance immunosuppressive therapy.

Methods

In this single-centre, open, randomized, four-sequence, four-treatment crossover study, the influence of PAN 40 mg on MPA pharmacokinetics such as (dose-adjusted) AUC_0–12 h (dAUC) was analysed in 20 renal transplant patients (>6 months post-transplantation) receiving MMF (1–2 g day^–1) and EC-MPS in combination with ciclosporin. The major metabolite MPA glucuronide (MPAG) and the IMPDH activity were also examined.

Results

MMF + PAN intake led to a lowest mean dAUC for MPA of 41.46 ng h ml^–1 mg^–1 [95% confidence interval (CI) 32.38, 50.54], while MPA exposure was highest for EC-MPS + PAN [dAUC: 46.30 ng h ml^–1 mg^–1 (95% CI 37.11, 55.49)]. Differences in dAUC and dose-adjusted maximum concentration (dCmax) were not significant. Only for MMF [dAUC: 41.46 ng h ml^–1 mg^–1 (95% CI 32.38, 50.54)] and EC-MPS [dAUC: 43.39 ng h ml^–1 mg^–1 (95% CI 33.44, 53.34)] bioequivalence was established for dAUC [geometric mean ratio: 101.25% (90% CI 84.60, 121.17)]. Simultaneous EC-MPS + PAN intake led to an earlier time to Cmax (tmax) [median: 2.0 h (min–max: 0.5–10.0)] than EC-MPS intake alone [3 h (1.5–12.0); P = 0.037]. Tmax was not affected for MMF [1.0 h (0.5–5.0)] ± pantoprazole [1.0 h (0.5–6.0), P = 0.928). No impact on MPAG pharmacokinetics or IMPDH activity was found.

Conclusion

Pantoprazole influences EC-MPS and MMF pharmacokinetics but as it had no impact on MPA pharmacodynamics, the immunosuppressive effect of the drug was not impaired.     

Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents

Aim

In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its metabolites in overweight and obese adolescents.

Methods

Overweight (BMI for age ≥ 85^th percentile) and obese (BMI for age ≥ 95^th percentile) adolescents undergoing surgery received 2 or 3 mg intravenous midazolam as a sedative drug pre-operatively. Blood samples were collected until 6 or 8 h post-dose. Population pharmacokinetic modelling and systematic covariate analysis were performed using nonmem 7.2.

Results

Nineteen overweight and obese patients with a mean body weight of 102.7 kg (62–149.8 kg), a mean BMI of 36.1 kg m⁻² (24.8–55 kg m⁻²), and a mean age of 15.9 years (range 12.5–18.9 years) were included. In the model for midazolam and metabolites, total body weight was not of influence on clearance (0.66 l min⁻¹ (RSE 8.3%)), while peripheral volume of distribution of midazolam (154 l (11.2%)), increased substantially with total body weight (P < 0.001). The increase in peripheral volume could be explained by excess body weight (WT_excess) instead of body weight related to growth (WT_{for age and length}).

Conclusions

The pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents show a marked increase in peripheral volume of distribution and a lack of influence on clearance. The findings may imply a need for a higher initial infusion rate upon initiation of a continuous infusion in obese adolescents.     

Population pharmacokinetics of deferiprone in healthy subjects

Aims

To characterize the pharmacokinetics of deferiprone in healthy subjects using a model-based approach and to assess the effect of demographic and physiological factors on drug exposure.

Methods

Data from 55 adult healthy subjects receiving deferiprone (solution 100 mg ml⁻¹) were used for model building purposes. A population pharmacokinetic analysis was performed using nonmem v.7.2. The contribution of gender, age, weight and creatinine clearance (CL_cr) on drug disposition was evaluated according to standard forward inclusion, backward deletion procedures. Model selection criteria were based on graphical and statistical summaries.

Results

A one compartment model with first order oral absorption was found to describe best the pharmacokinetics of deferiprone. Simulated exposure values were comparable with previously published data. Mean AUC estimates were 45.8 and 137.4 mg l⁻¹ h, whereas C_max increased from 17.6 to 26.5 mg l⁻¹ after administration of 25 and 75 mg kg⁻¹ doses, respectively. Gender differences in the apparent volume of distribution (20%) have been identified, which are unlikely to be of clinical relevance. Furthermore, simulation scenarios reveal that dose adjustment is required for patients with reduced CL_cr. Doses of 60, 40 and 25 mg kg⁻¹ for patients showing mild, moderate and severe renal impairment are proposed based on CL_cr values of 60–89, 30–59 and 15–29 ml min⁻¹, respectively.

Conclusions

Our analysis has enabled the assessment of the impact of gender and CL_cr on the pharmacokinetics of deferiprone. Moreover, it provides the basis for dosing recommendations in renal impairment. The implication of these covariates on systemic exposure is currently not available in the prescribing information of deferiprone.     

Estimation of drug receptor occupancy when non-displaceable binding differs between brain regions – extending the simplified reference tissue model

AimThe simplified reference tissue model (SRTM) is used for estimation of receptor occupancy assuming that the non-displaceable binding in the reference region is identical to the brain regions of interest. The aim of this work was to extend the SRTM to also account for inter-regional differences in non-displaceable concentrations, and to investigate if this model allowed estimation of receptor occupancy using white matter as reference. It was also investigated if an apparent higher affinity in caudate compared with other brain regions, could be better explained by a difference in the extent of non-displaceable binding.MethodsThe analysis was based on a PET study in six healthy volunteers using the 5-HT_1B receptor radioligand [¹¹C]-AZ10419369. The radioligand was given intravenously as a tracer dose alone and following different oral doses of the 5-HT_1B receptor antagonist AZD3783. Non-linear mixed effects models were developed where differences between regions in non-specific concentrations were accounted for. The properties of the models were also evaluated by means of simulation studies.ResultsThe estimate (95% CI) of Ki_PL was 10.2 ng ml⁻¹ (5.4, 15) and 10.4 ng ml⁻¹ (8.1, 13.6) based on the extended SRTM with white matter as reference and based on the SRTM using cerebellum as reference, respectively. The estimate (95% CI) of Ki_PL for caudate relative to other brain regions was 55% (48, 62%).ConclusionsThe extended SRTM allows consideration of white matter as reference region when no suitable grey matter region exists. AZD3783 affinity appears to be higher in the caudate compared with other brain regions.     

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

AIM

The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP₁ antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 µg).

METHOD

GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 µg). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography-tandem mass spectrometry method following solid phase extraction.

RESULTS

Following the i.v. microdose, the geometric mean values for clearance (CL), steady-state volume of distribution (V_ss) and terminal elimination half-life (t_1/2) of GSK269984A were 9.8 l h⁻¹, 62.8 l and 8.2 h. C_max and AUC(0,∞) were 3.2 ng ml⁻¹ and 10.2 ng ml⁻¹ h, respectively; the corresponding oral parameters were 1.8 ng ml⁻¹ and 9.8 ng ml⁻¹ h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre-clinical species (rat, dog and monkey).

CONCLUSION

For drug development programmes characterized by inconsistencies between pre-clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development.     

Histamine-induced vasodilatation in the human forearm vasculature

Aim

To investigate the mechanism of action of intra-arterial histamine in the human forearm vasculature.

Methods

Three studies were conducted to assess changes in forearm blood flow (FBF) using venous occlusion plethysmography in response to intra-brachial histamine. First, the dose–response was investigated by assessing FBF throughout a dose-escalating histamine infusion. Next, histamine was infused at a constant dose to assess acute tolerance. Finally, a four way, double-blind, randomized, placebo-controlled crossover study was conducted to assess FBF response to histamine in the presence of H₁- and H₂-receptor antagonists. Flare and itch were assessed in all studies.

Results

Histamine caused a dose-dependent increase in FBF, greatest with the highest dose (30 nmol min⁻¹) infused [mean (SEM) infused arm vs. control: 26.8 (5.3) vs. 2.6 ml min⁻¹ 100 ml⁻¹; P < 0.0001]. Dose-dependent flare and itch were demonstrated. Acute tolerance was not observed, with an increased FBF persisting throughout the infusion period. H₂-receptor antagonism significantly reduced FBF (mean (95% CI) difference from placebo at 30 nmol min⁻¹ histamine: −11.9 ml min⁻¹ 100 ml⁻¹ (−4.0, −19.8), P < 0.0001) and flare (mean (95% CI) difference from placebo: −403.7 cm² (−231.4, 576.0), P < 0.0001). No reduction in FBF or flare was observed in response to the H₁-receptor antagonist. Itch was unaffected by the treatments. Histamine did not stimulate vascular release of tissue plasminogen activator or von Willebrand factor.

Conclusion

Histamine causes dose-dependent vasodilatation, flare and itch in the human forearm. H₂-receptors are important in this process. Our results support further exploration of combined H₁- and H₂-receptor antagonist therapy in acute allergic syndromes.     

Dried blood spots and sparse sampling: a practical approach to estimating pharmacokinetic parameters of caffeine in preterm infants

Aims

Dried blood spots (DBS) alongside micro‐analytical techniques are a potential solution to the challenges of performing pharmacokinetic (PK) studies in children. However, DBS methods have received little formal evaluation in clinical settings relevant to children. The aim of the present study was to determine a PK model for caffeine using a ‘DBS/microvolume platform’ in preterm infants.

Methods

DBS samples were collected prospectively from premature babies receiving caffeine for treatment of apnoea of prematurity. A non‐linear mixed effects approach was used to develop a population PK model from measured DBS caffeine concentrations. Caffeine PK parameter estimates based on DBS data were then compared with plasma estimates for agreement.

Results

Three hundred and thirty‐eight DBS cards for caffeine measurement were collected from 67 preterm infants (birth weight 0.6–2.11 kg). 88% of cards obtained were of acceptable quality and no child had more than 10 DBS samples or more than 0.5 ml of blood taken over the study period. There was good agreement between PK parameters estimated using caffeine concentrations from DBS samples (CL = 7.3 ml h⁻¹ kg⁻¹; V = 593 ml kg⁻¹; t_1/2 = 57 h) and historical caffeine PK parameter estimates based on plasma samples (CL = 4.9–7.9 ml h⁻¹ kg⁻¹; V = 640–970 ml kg⁻¹; t_1/2 = 101–144 h). We also found that changes in blood haematocrit may significantly confound estimates of caffeine PK parameters based on DBS data.

Conclusions

This study demonstrates that DBS methods can be applied to PK studies in a vulnerable population group and are a practical alternative to wet matrix sampling techniques.