Pharmacokinetics and Mammary Residual Depletion of Erythromycin in Healthy Lactating Ewes

The aim of this investigation was to examine the pharmacokinetics and mammary excretion of erythromycin administered to lactating ewes (n = 6) by the intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) routes at a dosage of 10 mg/kg. Blood and milk samples were collected at pre‐determined times, and a microbiological assay method was used to measure erythromycin concentrations in serum and milk. The concentration–time data were analysed by compartmental and non‐compartmental kinetic methods. The serum concentration–time data of erythromycin were fit to a two‐compartment model after i.v. administration and a one‐compartment model with first‐order absorption after i.m. and s.c. administration. The elimination half‐life (t_1/2β) was 4.502 ± 1.487 h after i.v. administration, 4.874 ± 0.296 h after i.m. administration and 6.536 ± 0.151 h after s.c. administration. The clearance value (Cl_tot) after i.v. dosing was 1.292 ± 0.121 l/h/kg. After i.m. and s.c. administration, observed peak erthyromycin concentrations (C_max) of 0.918 ± 0.092 μg/ml and 0.787 ± 0.010 μg/ml were achieved at 0.75 and 1.0 h (T_max) respectively. The bioavailability obtained after i.m. and s.c. administration was 91.178 ± 10.232% and 104.573 ± 9.028% respectively. Erythromycin penetration from blood to milk was quick for all the routes of administration, and the high AUC_milk/AUC_serum (1.186, 1.057 and 1.108) and C_max‐milk/C_max‐serum ratios reached following i.v., i.m. and s.c. administration, respectively, indicated an extensive penetration of erythromycin into the milk.     

Pharmacokinetics of mycophenolic acid, tacrolimus and sirolimus after gastric bypass surgery in end-stage renal disease and transplant patients: a pilot study

Abstract: Background: Promising data regarding the safety and efficacy of gastric bypass surgery (GBS) as an option to address obesity in the transplant population are emerging. The data lack on how GBS may alter the pharmacokinetics (PK) of modern immunosuppression. The objective of this study was to describe the alterations in the PK of modern immunosuppressants and the GBS population. Methods: Data are presented on six subjects who participated in this trial – four were on dialysis and two were renal transplant recipients. Dialysis‐dependent bypass subjects received a single dose of 6 mg of sirolimus, two 4‐mg doses of tacrolimus and two 1000‐mg doses of mycophenolate mofetil (MMF) over the 24‐h study period. Transplant recipients continued their current regimen. Maximum plasma concentration (C_max), time to reach the maximum plasma concentration (T_max) and the area under the plasma concentration vs. time curve (AUC_0–12 and AUC_0–∞ where appropriate) were calculated for tacrolimus, sirolimus, mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG). Results: Significant inter‐patient variability in the C_max, T_max and AUC of tacrolimus, sirolimus MPA and MPAG was observed. A notable difference in the AUC:dose ratio for tacrolimus was seen when comparing data with published data in the non‐bypass population. Similar differences in PK were seen with sirolimus, MPA and MPAG. Conclusions: When comparing the PK of sirolimus, tacrolimus, MPA and MPAG to published PK data in the non‐bypass population, significant differences are observed. It is likely that transplant recipients with GBS would need higher doses of tacrolimus, sirolimus and MMF to provide similar exposure to a non‐bypass patient.     

Pharmacokinetic profile of tamsulosin OCAS

The tamsulosin oral‐controlled absorption system (OCAS®) is a new tablet formulation of the α₁‐adrenoceptor (α₁‐AR) antagonist tamsulosin, which is used for treating lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). The tablet uses the OCAS technology, which was specifically designed to give a more continuous 24‐h release of tamsulosin, resulting in a more consistent and continuous 24‐h plasma concentration, a lower maximum plasma concentration (C_max) and an independence of pharmacokinetics (PKs) on food intake. It was expected that the improved PK profile would translate into a better control of day‐ and night‐time symptoms of BPH and a lower risk of adverse events. Phase I PK studies showed that tamsulosin OCAS indeed has a flattened PK profile with a lower C_max and a more stable and consistent 24‐h concentration of tamsulosin, independent of food intake, compared to conventional tamsulosin. A study combining γ‐scintigraphy and PK analysis of blood samples confirmed that the improved PK profile of tamsulosin OCAS is attributed to the tablet being consistently and continuously released throughout the entire gastrointestinal tract, including the colon.     

Influence of Escherichia coli Endotoxin‐Induced Endotoxaemia on the Pharmacokinetics of Enrofloxacin after Intravenous Administration in Rabbits

The main goal of present study was to determine the effects of an Escherichia coli endotoxin‐induced endotoxaemic status on disposition of enrofloxacin after a single intravenous dose (5 mg/kg) in rabbits. Septic shock was induced by the i.v. bolus administration at a single dose of E. coli lipopolysaccharide. Six adult New Zealand White rabbits were used. Concentrations of drug in plasma were determined by HPLC. The plasma pharmacokinetic values for enrofloxacin were best represented using a two‐compartment open model. Total plasma clearance (Cl_T) decreased from 2.11 (l/h/kg) in healthy animals to 1.50 (l/h/kg) in rabbits with septic shock, which is related to an increase in the AUC_0→∞. In endotoxaemic rabbits, volume of distribution at steady state (V_dss = 3.61 l/kg) was significantly lower (P < 0.05) than in healthy animals (V_dss = 4.97 l/kg). However, the elimination half‐life of enrofloxacin was not affected by lipopolysaccharide administration.     

Oral bioavailability of clonidine in children

Background: Oral clonidine is used as premedication in children. The bioavailability of clonidine given orally in adults is 75–100% but is unknown in children. Methods: Children (3–10 years) undergoing adenotonsillectomy were administered oral clonidine 4 mcg·kg^?1 mixed with apple fruit drink as premedication. Intravenous plasma was assayed for clonidine concentration at 5, 15, 30, 45 min and 1, 2, 4, 6, 12, 18 h after administration. Clonidine plasma concentrations were determined by liquid chromatography‐mass spectroscopy, and pharmacokinetic parameters were calculated using nonlinear effects mixed‐effects models. Current data were pooled with published time–concentration profiles from children (n = 49) administered intravenous clonidine to determine oral bioavailability. Results: There were eight children studied (age 3–10 years, weight 10.5–36 kg). A two‐compartment model with first‐order absorption and elimination was used to describe time–concentration profiles. Population parameter estimates (CV%; 95% CI), standardized to a 70‐kg person, were absorption half‐life (Tabs), 0.45 (85.1; 0.221–0.884) h, absorption lag time (Tlag), 0.148 (91.2; 0.002–0.316) h, Clearance (CL) 17.9 (30.3; 16–20.3) l·h^?1 per 70 kg, between compartment clearance (Q) 121 (44.3; 80.1–165) l·h^?1 per 70 kg, central volume (V1) 81.2 (71.5; 60.7–105) l·70 kg^?1, peripheral volume of distribution (V2) 113 (33.9; 91–131) l·70 kg^?1. The oral bioavailability was 55.4% (CV 6.4%; 95% CI 0.469, 0.654). Conclusions: Clonidine administered with an apple fruit drink displays a variable and relatively slow absorption after oral administration (T_max 1.04 h, C_max 0.77 mcg·l^?1). The oral bioavailability was 55.4%, which is less than reported in adults. Consequently, higher oral doses of clonidine (per kg) are required when this formulation is used to achieve concentrations similar to those reported in adults.     

Pharmacokinetic and pharmacodynamic study of intranasal and intravenous dexmedetomidine

Background

Intranasal dexmedetomidine produces safe, effective sedation in children and adults. It may be administered by drops from a syringe or by nasal mucosal atomisation (MAD Nasal^TM).

A comparative study of FK506 granules and capsules in renal transplant recipients

Nine renal transplant recipients in stable systemic condition on FK506 capsules were converted to FK506 granules in order to investigate the safety, efficacy, and pharmacokinetics of the granular formulation of FK506. The study period for the administration of FK506 granules was 4 weeks, and in principle, the oral dose was the same as that of the FK506 capsules. Renal graft function remained stable and no rejection signs were noticed while the patients were taking the granules. The area under the blood concentration-time curve (AUC), the maximum blood level (C_max), and the time to reach C_max (T_max) after FK506 capsules and FK506 granules were, respectively, 93.1 ± 66.4 and 97.0 ± 89.1 ng · h/ml (P = 0.81), 12.7 ± 7.1 and 15.2 ± 11.7 ng/ml (P = 0.39), and 2.0 ± 1.7 and 1.3 ± 0.6 h (P = 0.29). The mean trough blood level during FK506 medication was 4.25 ± 3.42 and 4.02 ± 3.83 ng/ml, respectively, for the capsules and the granules. FK506 granules, a new formulation, showed an efficacy comparable to that of the FK506 capsular formulation. Received: 28 July 1997 Received after revision: 25 November 1997 Accepted: 14 January 1998     

Pharmacokinetics of ganciclovir in pediatric renal transplant recipients

Ganciclovir (GCV) is effective in preventing and treating cytomegalovirus (CMV) infection in solid organ transplant recipients. The aims of the present study were to determine the pharmacokinetics of GCV administered intravenously (IV) and orally (p.o.) as pre-emptive anti-CMV therapy in pediatric renal transplant recipients and to monitor trough levels and side-effects during pre-emptive therapy. Eleven pediatric renal transplant recipients (aged 11.0±3.9 years) were included. The diagnosis of CMV infection, based on two positive pp-65 CMV blood antigen tests at 1 week apart, was made at 39±12 days post renal transplantation. They received IV GCV at a dose of 5.0±0.3 mg/kg per 12 h for 15 days, followed by GCV p.o. at a dose of 46.7±8.2 mg/kg per 12 h for 3 months. Pharmacokinetics (PK) were studied at steady state and GCV plasma concentrations were measured by high-performance liquid chromatography. After IV GCV administration, PK parameters were: C₀=0.84±0.66 g/ml; C_max=11.77±2.82 g/ml; AUC_{0–12 h}=42.29±17.57 g/ml per hour; Cl=0.13±0.05 l/h per kg. After p.o. GCV administration, PK parameters were: C₀=1.08±0.68 g/ml; C_max=2.70±1.07 g/ml; AUC_{0–12 h}=18.97±9.36 g/ml per hour; Cl/F=2.97±1.42 l/h per kg. Bioavailability (F) was 4.9±1.2%. Pre-dose concentrations (C₀) measured under p.o. GCV (n=51) were 1.29±0.80 g/ml (8 C₀ values were below 0.5 µg/ml). Pp-65 CMV blood antigen tests became negative after 16±11 days of treatment. GCV was well tolerated. Because of the limited bioavailability, the recommended high doses of p.o. GCV (50 mg/kg per 12 h) were administered and were associated with trough levels over 0.5 µg/ml. In 1 patient who received an erroneously low dosage p.o., CMV resistance to GCV appeared, requiring foscarnet.     

Pharmacokinetics,Urinary and Mammary Excretion of Ceftriaxone in Lactating Goats

The pharmacokinetic properties of ceftriaxone were investigated in 10 goats following a single intravenous (i.v.) and intramuscular (i.m.) administration of 20 mg kg⁻¹ body weight. After i.v. injection, ceftriaxone serum concentration–time curves were characteristic of a two‐compartment open model. The distribution and elimination half‐lives (t_1/2α, t_1/2β) were 0.12 and 1.44 h respectively. Following i.m. injection, peak serum concentration (C_max) of 23.6 μg ml⁻¹ was attained at 0.70 h. The absorption and elimination half‐lives (t_1/2ab, t_1/2el) were 0.138 and 1.65 h respectively. The systemic bioavailability of the i.m. administration (F %) was 85%. Following i.v. and i.m. administration, the drug was excreted in high concentrations in urine for 24 h post‐administration. The drug was detected at low concentrations in milk of lactating goats. A recommended dosage of 20 mg kg⁻¹ injected i.m. every 12 h could be expected to provide a therapeutic serum concentration exceeding the minimal inhibitory concentrations for different susceptible pathogens.     

Population pharmacokinetics of intravenous bolus etomidate in children over 6 months of age

Background: Information has been very limited on the population pharmacokinetics (PK) of etomidate in pediatric patients. The purpose of this study was to characterize the PK of etomidate in children. Methods: Forty‐nine children aged over 6 months undergoing elective surgery received etomidate 0.3 mg·kg^?1 bolus i.v. within 15 s for anesthesia induction. Arterial blood samples were collected for 2 h after injection. A population nonlinear mixed effects modeling approach was used to characterize etomidate PK. Estimates were standardized to a 70‐kg adult using allometric size models. Results: Children had a median age of 4 years (0.53–13.21 years) and weight 15.7 kg (7.5–52 kg). PK of etomidate was best estimated using a three‐compartment model with weight on systemic (Cl₁) and inter‐compartmental clearances (Cl₂, Cl₃), central (V₁), and peripheral compartment volumes (V₂, V₃). The most significant PK covariate was age, with increasing age having reduced size‐adjusted Cl₁, V₁, and V₃ (all P < 0.01). The estimates of PK parameter (standardized to 70‐kg adult) for a typical 4‐year‐old children were Cl₁ = 1.50 l·min^?1, Cl₂ = 1.95 l·min^?1, Cl₃ = 1.23 l·min^?1, V₁ = 9.51 l, V₂ = 11.0 l, and V₃ = 79.2 l, respectively. Conclusions: Owing to enhanced clearance and increased central compartment volume of etomidate, smaller (younger) children will require higher etomidate bolus dose than larger (older) children to achieve equivalent plasma concentrations. The dependence of Cl₁ and V₁ on age does not support weight‐based etomidate dosing in smaller children.     

Pharmacokinetics of recombinant human erythropoietin applied subcutaneously to children with chronic renal failure

The single-dose pharmacokinetics of recombinant human erythropoietin (rHuEPO) given SC was investigated in 20 patients aged 7–20 years at different stages of chronic renal failure. In a pilot study we confirmed the lower bioavailability of the drug in 2 children when given SC compared with the IV route (24% and 43%, respectively). Following administration of 4,000 units/m², rHuEPO SC effective serum erythropoietin concentrations increased from a mean baseline level (±SD) of 23±13 units/l to a mean peak concentration of 265±123 units/l, which was reached after 14.3±9.4 h, followed by a slow decline until baseline values were attained at 72 h. Mean residence time was 30±9 h and mean elimination half-time 14.3±7 h. The single-dose kinetics of SC rHuEPO in children with different degrees of renal failure are comparable to those in adult patients. Possibly, the higher efficacy of SC rHuEPO in patients with renal anaemia compared with IV rHuEPO is related to its prolonged action.     

Effect of a water‐based no‐sting,protective barrier formulation and a solvent‐containing similar formulation on skin protection from medical adhesive trauma

Trauma to the skin from repeated removal of adhesive‐based medical products can cause pain, anxiety, risk of secondary infections and additional health care costs. Skin barrier formulations are used to protect the integrity from such trauma. However, not all formulations are equally protective. We report the results of a randomised controlled study comparing a solvent‐free (SF) formulation and a solvent‐containing (SC) formulation to the skin of 12 healthy volunteers aged 18–55 years. Treatments were applied at baseline to two of the four test sites on the back of each subject and repeated for 5 days. Measurements of pain, discomfort, erythema and skin water loss were taken 24 hours after each application. The SF formulation is associated with lower mean scores for erythema (day 5, P < 0·05) and lower values for transepidermal water loss (day 5, P < 0·05) and redness (days 4 and 5, P < 0·05) when compared with either no treatment or daily treatment with a SC formulation. There were no significant differences between subject responses when pain on application of the test formulation or discomfort associated with removal of the medical adhesive tapes were rated. We conclude that a SF formulation provides better security against adhesive‐derived skin trauma than a SC formulation.     

Effects of novel cathepsin K inhibitor ONO-5334 on bone resorption markers: a study of four sustained release formulations with different pharmacokinetic patterns

The purpose of the study was clarify the effect of the cathepsin K inhibitor ONO-5334 on bone resortion markers using sustained release (SR) formulations with different pharmacokinetic (PK) patterns, and identify the optimal SR formulation. The PK profiles and pharmacodynamic effect on bone resorption markers of 4 SR candidates formulations were evaluated in healthy postmenopausal women within a randomized, 2-part, open-label crossover study. In Part A, subject received a single dose of each formulation orally in the fed state. In Part B, two selected formulations were evaluated in the fasted state. From the results from Part A, C _max was reduced and plasma concentrations of ONO-5334 were sustained with all SR formulations compared with an immediate release tablet. In pharmacodynamics, the level of C-terminal telopeptide of type I collagen (CTX) in serum and urine were inhibited with SR tablets rather than with granules. C _max and area under the concentration–time curve from time 0 to the last measurable time point (AUC_0?t ) of SR tablets were higher than those of granules. From Part B, C _max in the fasted condition was lower than that in the fed condition with two SR tablets. In contrast, C _{24 h} in the fasted condition was slightly higher than that in the fed condition, but AUC_0?t was similar. The inhibitory effect on CTX in serum and urine may depend on the PK pattern of ONO-5334. The SR tablets was well tolerated in postmenopausal women and has the optimal SR profiles on pharmacodynamics effect on bone resortion markers and PK profile. These results suggest that SR tablets of ONO-5334 are an excellent drug candidate for osteoporosis.     

Plasma Profiles of Ivermectin in Horses following Oral or Intramuscular Administration

A study was undertaken in order to evaluate and compare ivermectin's (IVM) plasma disposition kinetic parameters after oral or intramuscular (IM) administration in horses. Ten clinically healthy adult horses, weighing 380–496 kg body weight (BW), were allocated to two experimental groups of five horses. Group I, was treated with an oral paste formulation of IVM at the manufacturer's recommended dose of 0.2 mg/kg BW. Group II, was treated IM with an injectable 1% formulation of IVM at a dose of 0.2 mg/kg BW. Blood samples were collected by jugular puncture at different times between 0.5 h and 75 days post‐treatment. After plasma extraction and derivatization, samples were analysed by high‐performance liquid chromatography with fluorescence detection. A computerized kinetic analysis was performed, and data were compared using the Wilcoxon signed rank test. The parent molecule was detected in plasma between 30 min and either 20 (oral) or 40 (IM) days post‐treatment. Significant differences were found for the time corresponding to peak plasma concentrations (t_max) and for absorption half‐life. Peak plasma concentrations (C_max) of 51.3 ± 16.1 ng/ml (mean ± SD) were obtained after oral administration and of 31.4 ± 6.0 ng/ml for the IM route. The values for area under concentration–time curve were 137.1 ± 35.9 ng day/ml for the group treated orally, and 303.2 ± 4.3 ng day/ml for the IM treated group. The mean plasma residence times were 4.2 ± 0.4 and 8.9 ± 0.7 days for oral and IM‐treated groups, respectively. The results of this study show that the route of administration considerably affects the disposition of IVM. A significant difference in bioavailabilty and half‐life of elimination of IVM was observed after IM administration compared with oral administration. A close relationship between pharmacokinetic profiles and the clinical efficacy of IVM was established.     

A randomized,crossover pharmacokinetic study comparing generic tacrolimus vs. the reference formulation in subpopulations of kidney transplant patients

An exploratory, post hoc analysis was performed using data from a prospective, multicenter, open‐label, randomized, two‐period (14 d per period), two‐sequence, crossover, steady‐state pharmacokinetic study comparing generic tacrolimus (Sandoz) vs. reference tacrolimus in stable renal transplant patients receiving their pre‐study twice‐daily dose. Pharmacokinetic parameters were compared in 68 patients according to gender, African American ethnicity, the presence or absence of diabetes, and use of steroids. The ratios of tacrolimus AUC_0–12 h, C_max, and C₁₂ with generic vs. reference tacrolimus were calculated using the geometric mean (GM) of dose‐normalized values at days 14 and 28. Mean (SD) tacrolimus dose at baseline was 5.7 (4.2) mg/d. There were no consistent differences in dose‐normalized AUC_0–12 h, C₁₂, C_max, or t_max between the generic and reference preparations within subpopulations. The 90% confidence intervals (CI) for the ratios of dose‐normalized AUC_0–12 h and C₁₂ with generic vs. reference tacrolimus were within 80–125% for all subpopulations, as were 90% CIs for C_max other than for females, African Americans, and non‐diabetics, which is not unexpected given the wide variability of tacrolimus C_max and the small subpopulation sizes. These exploratory results suggest that this generic tacrolimus preparation would be expected to offer comparable bioavailability to the reference drug in these patient subpopulations.     

Comparative Pharmacokinetics of Theophylline in Camels (Camelus dromedarius) and Goats (Caprus hircus)

A comparative randomized crossover study was conducted to determine the pharmacokinetics of theophylline in male and female camels (Camelus dromedarius) and goats (Caprus hircus). Theophylline is an established `probe drug' to evaluate the drug metabolizing enzyme activity of animals. It was administered by the intravenous (i.v.) route and then intramuscularly (i.m.) at a dose of 2 mg/kg. The concentration of the drug in plasma was measured using a high‐performance liquid chromatography (HPLC) technique on samples collected at frequent intervals after administration. Following i.v. injection, the overall elimination rate constant (λ_z) in goats was 0.006 ± 0.00076/min and in camels was 0.0046 ± 0.0008/min (P < 0.01). The elimination half‐life (t_1/2λz) in goats (112.7 min) was lower than in camels (154.7 min) (P < 0.01). The apparent volume of distribution (V_z) and the total body clearance (Cl) in goats were 1440.1 ± 166.6 ml/kg and 8.9 ± 1.4 ml/min/kg, respectively. The corresponding values in camels were 1720.3 ± 345.3 ml/kg and 6.1 ± 1.0 ml/min/kg, respectively. After i.m. administration, theophylline reached a peak plasma concentration (C_max) of 1.8 ± 0.1 and 1.7 ± 0.2 μg/ml at a post‐injection time (T_max) of 67.5 ± 8.6 and 122.3 ± 6.7 min in goats and camels, respectively. The mean bioavailability (F) in both goats and camels was 0.9 ± 0.2. The above data suggest that camels eliminate theophylline at a slower rate than goats.     

Efficacy of ketamine and midazolam as co-induction agents with propofol for laryngeal mask insertion in children

Objectives: Use of midazolam and ketamine lowers the induction dose of propofol (co‐induction) producing hemodynamic stability. Background: Large doses of propofol needed for induction and laryngeal mask (LM) insertion in children may be associated with hemodynamic and respiratory effects. Co‐induction has the advantage of reducing dose and therefore maintaining hemodynamic stability. Aim: To examine the effect of co‐induction on hemodynamics, LM insertion and recovery in children. Methods/Materials: A prospective, randomized, double‐blind, controlled study was conducted in 60 ASA I/II children, age 1–8 years. Normal saline, ketamine 0.5 mg·kg^?1, midazolam 0.05 mg·kg^?1 were administered in groups P (propofol), PK (propofol–ketamine) and PM (propofol–midazolam), respectively, 2 min prior to the administration of the induction dose of propofol. Propofol 3.5 mg·kg^?1 (group P) or 2.5 mg·kg^?1 (groups PK and PM) was used for induction, LM inserted 30 s later and insertion conditions assessed. Heart rate and blood pressure were recorded immediately after propofol bolus, then every min till 2 min after LMA insertion. Recovery was assessed using Steward’s Score. Result: In group P, systolic blood pressure (SBP) showed a significantly greater decrease compared to group PK and group PM (P < 0.005). Only 5% of patients in groups PK and PM showed >20% fall in SBP compared to 89% in group P (P < 0.005). More children in groups PK and PM had acceptable conditions for LM insertion compared to group P (P < 0.05). The time to achieve Steward Score of 6 was longer in groups PK and PM compared to group P (P < 0.005). Conclusion: In children, the combination of propofol with ketamine or midazolam produces stable hemodynamics and improved LM insertion conditions but is associated with delayed recovery.     

Does intranasal dexmedetomidine provide adequate plasma concentrations for sedation in children: a pharmacokinetic study

Background

Atomised intranasal dexmedetomidine administration is an attractive option when sedation is required for paediatric diagnostic procedures, as vascular access is not required. The risk of haemodynamic instability caused by dexmedetomidine necessitates better understanding of its pharmacokinetics in young children. To date, intranasal dexmedetomidine pharmacokinetics has only been studied in adults.

Pharmacokinetic/Pharmacodynamic Modelling of Roxithromycin for the Inhibitory Effect of Tumour Necrosis Factor‐Alpha and Interleukin‐6 Production in Dogs

The objective of the present study was to determine and characterize the relationship between the plasma concentration of roxithromycin, and its inhibitory effect on cytokine production, in order to predict its possible clinical relevance. Six healthy beagle dogs received a single intravenous dose of 20‐mg roxithromycin per kg body weight. Blood samples were obtained at different time points. The plasma was analysed with respect to roxithromycin, tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6). The concentration–effect relationship was explored by modelling the data using two compartmental model and an indirect response model with an E_max concentration–effect relationship. The estimated pharmacokinetic parameters (geometric mean) were as follows: V_c = 2.59 l; k₁₀ = 0.08/h; k₁₂ = 0.26/h; k₂₁ = 0.40/h. The pharmacodynamic parameters (geometric mean) for the inhibitory effect on cytokine production induced by heat‐killed Staphylococcus aureus (HKSA) were for TNF‐α (k_in = 1.42 μg/h; k_out = 1.10 μg/h; EC₅₀ > 5.69 mg/l) and for IL‐6 (k_in = 2.31 μg/h; k_out = 2.04 μg/h; EC₅₀ = 21.07 mg/l) production, respectively. The inhibitory effect of roxithromycin on production can be adequately described by the indirect response model with an E_max concentration–effect relationship.