The pharmacokinetics of pioglitazone in patients with impaired renal function

AIMS: To evaluate the effect of renal impairment on the pharmacokinetics and safety of pioglitazone and its metabolites M-III and M-IV with impaired renal function and normal renal function. METHODS: In a phase-I, open-label, parallel-group study, six healthy subjects with normal renal function (creatinine clearance> 80 ml min-1), nine patients with moderate renal impairment (creatinine clearance 30-60 ml min-1) and 12 patients with severe renal impairment (creatinine clearance < 30 ml min-1) received single and multiple oral doses of pioglitazone 45 mg. The serum pharmacokinetic profiles of pioglitazone and its metabolites M-III and M-IV were assessed for the first and last dose administered (day 1 and day 12, respectively). RESULTS: Pharmacokinetic data revealed no significant accumulation of pioglitazone or its metabolites M-III and M-IV in patients with renal impairment. There was no significant difference in the pharmacokinetic profile of pioglitazone in subjects with normal and with moderately impaired renal function. After single oral doses, mean area under the concentration-time curve (AUC) values were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (13 476 vs 17 387, P = 0.371; -23%; confidence interval (CI) -57, 38), M-III metabolite (13 394 vs 15 071, P = 0.841; -11%; CI -74, 194) and M-IV metabolite (27 991 vs 49 856, P = 0.006; -44%; CI -62, -17). After repeated oral doses of pioglitazone, mean AUC values (microg.h l-1) were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (8744 vs 14,565, P = 0.004; -40%; CI -57, -16), M-III (3991 vs 7,289, P = 0.0009; -45%; CI -60, -25) and M-IV (21 080 vs 25 706, P = 0.181; -18%; CI 39, 10). The tolerability and safety profile of pioglitazone was comparable between groups. CONCLUSIONS: Pioglitazone was well tolerated in patients with varying degrees of renal impairment. Although mean serum concentrations of pioglitazone and its metabolites are increased in patients with severe renal impairment, adjustment of starting and maintenance doses in these patients is probably unwarranted.     

Effect of severe renal impairment on the pharmacokinetics of azimilide following single dose oral administration

AIMS: To assess the influence of severe renal impairment on azimilide pharmacokinetics. METHODS: A single oral dose of 125 mg azimilide dihydrochloride was administered to subjects with normal and severely impaired renal function. Blood and urine samples were collected for 22-28 and 10 days, respectively. RESULTS: Azimilide renal clearance decreased in subjects with renal impairment (mean 14 vs 4.8 ml h-1 kg-1, 95% confidence interval on the ratio 0.23, 0.50). However, no change in any other pharmacokinetic parameter including oral clearance (mean 109 vs 104 ml h-1 kg-1, 95% confidence interval on the ratio 0.67, 1.36) was observed. CONCLUSIONS: Since azimilide blood concentrations are essentially unaffected by renal function, an a priori dosage regimen adjustment is not required in patients with renal impairment.     

Meloxicam pharmacokinetics in renal impairment

Aims The aim of the present study was to determine how the pharmacokinetics of meloxicam are affected by kidney dysfunction and consequently to define the appropriate dose for the use of meloxicam in patients with mild or moderate renal impairment.
Methods Meloxicam was administered to subjects with mild (creatinine clearance 41–60 ml min⁻¹) to moderate (20–40 ml min⁻¹) renal impairment compared with normal renal function (>60 ml min⁻¹). Thirty-eight subjects received meloxicam 15 mg once daily over 9 days. Meloxicam plasma concentrations were determined from blood samples taken during the study and pharmacokinetic parameters calculated according to noncompartmental methods.
Results Subjects with no or mild renal impairment showed sinular pharmacokinetic profiles (geometric mean AUC_SS (%gCV) 55 (33%) vs 55 (38%) μg ml⁻¹ h). Subjects with moderate renal impairment demonstrated lower total plasma meloxicam concentrations (AUC_SS 35 (50%) μg ml ⁻¹ h, with corresponding higher plasma clearance ( P = 0.013) compared with subjects with no renal impairment. However, this was combined with higher meloxicam free fractions in moderately impaired subjects such that free meloxicam concentrations were similar in all three groups. Meloxicam was well tolerated with few adverse events occurring and no difference in incidence observable between groups.
Conclusions On the basis of these results there is no necessity for a dosage adjustment when administering meloxicam to patients with mild to moderate renal impairment.     

Influence of hepatic impairment on pharmacokinetics of the human GLP-1 analogue, liraglutide

AIMS

To compare the pharmacokinetics (PK) of a single-dose of liraglutide in subjects with hepatic impairment.

METHODS

This parallel group, open label trial involved four groups of six subjects with healthy, mild, moderate and severe hepatic impairment, respectively. Each subject received 0.75 mg of liraglutide (s.c., thigh), and blood samples were taken over 72 h for PK assessment. Standard laboratory and safety data were collected. The primary endpoint was area under the plasma liraglutide concentration–time curve from time zero to infinity (AUC(0,∞)).

RESULTS

Exposure to liraglutide was not increased by hepatic impairment. On the contrary, mean AUC(0,∞) was highest for healthy subjects and lowest for subjects with severe hepatic impairment (severe/healthy: 0.56, with 90% CI 0.39, 0.81) and equivalence in this parameter across groups was not demonstrated. C_max also tended to decrease with hepatic impairment (severe/healthy: 0.71, with 90% CI 0.52, 0.97), but t_max was similar across groups (11.3–13.2 h). There were no serious adverse events, hypoglycaemic episodes or clinically significant changes in laboratory parameters and liraglutide was considered well tolerated.

CONCLUSIONS

This study indicated no safety concerns regarding use of liraglutide in patients with hepatic impairment. Exposure to liraglutide was not increased by impaired liver function; rather, the results suggest a decreased exposure with increasing degree of hepatic impairment. However, data are not conclusive to suggest a dose increase of liraglutide. Thus, the results indicate that patients with type 2 diabetes mellitus and hepatic impairment can use standard treatment regimens of liraglutide. There is, however, currently limited clinical experience with liraglutide in patients with hepatic impairment.     

The effect of haemodialysis on the pharmacokinetics of tenoxicam in patients with end-stage renal disease

Summary We have studied the pharmacokinetics of tenoxicam after single and multiple oral doses of 20 mg in five patients (2 men and 3 women) with end-stage renal disease undergoing haemodialysis.After a single dose, tenoxicam had a half-life (t_1/2) of 33 h, an apparent clearance (CL·f^–1) of 4.3 ml·min^–1, and an apparent volume of distribution (V_z·f^–1) of 11.8 l. The maximum tenoxicam concentration (C_max) was 4.3 mg·l^–1 at a median t_max of 1.7 h. There were no significant differences between the values calculated from the pre- or post-dialyser port plasma samples.Tenoxicam plasma concentrations measured during once daily dosing before and after haemodialysis showed that tenoxicam does not accumulate.Our findings suggest that dosage adjustment may not be required in patients with end-stage renal disease on haemodialysis taking tenoxicam.     

The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites

We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated.The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2–2.5-times higher in patients with severe renal impairment (CL_CR<10 ml·min^–1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects.The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance.The maximum target dose in patients with slight renal impairment (CL_CR>30 ml·min^–1) should not be changed. In patients with moderate renal impairment (CL_CR10–30 ml·min^–1) it should be reduced by 50%. In patients with severe renal impairment (CL_CR<10 ml·min^–1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.     

Effect of renal function on risedronate pharmacokinetics after a single oral dose

AIMS: To determine the relationship between risedronate pharmacokinetics and renal function. METHODS: Risedronate was administered to adult men and women (n=21) with various degrees of renal function (creatinine clearance 15-126 ml min-1 ) as a single oral dose of 30 mg. Serum samples were obtained for 72 h after dosing, and urine samples were collected for 72 h after dosing and then periodically for 6 weeks. Risedronate concentrations were determined using an enzyme-linked immunosorbent assay (ELISA). Risedronate serum concentration-time and urinary excretion rate-time profiles were analysed simultaneously using nonlinear regression. RESULTS: Renal clearance and volume of distribution were linearly related to creatinine clearance (r2=0.854, P<0.001; and r2=0.317, P<0.01, respectively). Decreases in predicted renal clearance and volume of distribution of 82 and 69%, respectively, were observed when creatinine clearance decreased from 120 to 20 ml min-1. A 64% decrease in predicted oral clearance was observed when creatinine clearance decreased from 120 to 20 ml min-1 (P=0.064). Iohexol clearance, a predictor of renal function, produced similar results to those observed with creatinine clearance. Risedronate was well tolerated by the study population. CONCLUSIONS: Risedronate renal clearance was significantly related to a decrease in renal function. There was a consistent reduction in oral clearance with a decrease in creatinine clearance. However, based on the regression analysis, generally no dosage adjustment appears to be necessary for most patients with mild or moderate renal impairment (creatinine clearance >20 ml min-1 ).     

Effect of renal impairment on the pharmacokinetics of PD 0200390, a novel ligand for the voltage-gated calcium channel alpha-2-delta subunit

AIMS

To investigate the pharmacokinetics and safety of PD 0200390 in healthy subjects and subjects with renal impairment (RI) and to examine the relationship between oral and renal PD 0200390 clearance and estimated creatinine clearance (CLcr).

METHODS

In this open-label study, 26 subjects were categorized into four groups based on renal function: no RI (CLcr >80 ml min⁻¹; n= 6); mild RI (CLcr 51 to ≤80 ml min⁻¹; n= 6); moderate RI (CLcr >30 to 50 ml min⁻¹; n= 6); and severe RI (CLcr ≤30 ml min⁻¹; n= 8). Subjects received a single, oral dose of PD 0200390 25 mg. Noncompartmental pharmacokinetic parameters were determined from plasma and urine concentration–time data.

RESULTS

PD 0200390 was rapidly absorbed; mean time to maximum plasma concentration was 1.66–3.24 h. Mean half-life in subjects with normal renal function was 5.36 h, and increased with worsening RI. Oral (CL/F) and renal (CL_R) clearance rates decreased with deteriorating renal function, whereas area under the concentration–time curve (AUC_0–∞) values increased by 56, 117 and 436% in subjects with mild, moderate and severe RI, respectively, indicating increased PD 0200390 exposure. Regression analysis demonstrated that CL/F and CL_R correlated with CLcr (r= 0.953 and 0.961, respectively). PD 0200390 was well tolerated in subjects with mild, moderate or no RI. The most common adverse events were somnolence, dizziness and headache; these occurred with greatest intensity in the severe RI group.

CONCLUSIONS

PD 0200390 pharmacokinetic parameters (CL/F, CL_R and AUC_0–∞) vary predictably with decreases in renal function; therefore dose adjustment may be required in individuals with RI.     

Effect of renal impairment on the pharmacokinetics of bupropion and its metabolites

AIMS: To investigate the effect of kidney disease on bupropion pharmacokinetics and on cytochrome P450 (CYP) 2B6 activity as measured by bupropion hydroxylation. METHODS: In an open parallel group study, 17 healthy, nonsmoking subjects and 10 patients with impaired kidney function received a single 150 mg oral dose of sustained release bupropion. Plasma concentrations of bupropion and its metabolites were measured for up to 72 h. Subjects were genotyped for the CYP2B6 SNPs 1459 C>T, 785 A>G and 516 G>T. RESULTS: Bupropion AUC was 126% higher (P < 0.0001, 95% CI +72%, +180%), C(max) 86% higher (P = 0.001, 95% CI +40%, +131%), CL/F 63% lower (P = 0.001, 95% CI -29%, -96%), and t(1/2) 140% longer (P = 0.001, 95% CI +76%, +204%) in renally impaired patients. However, only minor changes were detected in the concentrations of the metabolites. In renally impaired subjects the hydroxybupropion : bupropion AUC ratio was decreased by 66% (P = < 0.0001, 95% CI -19%, -114%) and the hydrobupropion : bupropion AUC ratio by 69% (P = 0.001, 95% CI +8%, -146%) compared with controls. CONCLUSIONS: The CL/F of bupropion was significantly lower in subjects with renal impairment. Because the principal metabolites of bupropion possess similar pharmacological activity to the parent compound, dosage recommendations for patients with renal impairment cannot be given. A direct effect of renal impairment on CYP2B6 activity could not be demonstrated by the present study design.     

The pharmacokinetics and safety of darapladib in subjects with severe renal impairment

Aim

Darapladib is a potent and reversible orally active inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂). The aim of the study was to assess the effects of severe renal impairment on the pharmacokinetics and safety/tolerability of darapladib compared with normal renal function.

Methods

This was an open label, parallel group study of darapladib following 10 day once daily 160 mg oral dosing in subjects with normal (n = 8) and severe renal impairment (estimated glomerular filtration rate <30 ml min^–1 1.73 m^–2, n = 8). Plasma concentrations of total and unbound darapladib as well as total darapladib metabolites were determined in samples obtained over 24 h on day 10.

Results

Plasma concentrations of total and unbound darapladib as well as all three metabolites were higher in subjects with severe renal impairment. Area under the plasma concentration vs. time curve between time zero and 24 h (AUC(0,24 h) and maximum plasma concentration (C_max) of total darapladib in severely renally impaired subjects were 52% and 59% higher than those in the matched healthy subjects, respectively. Similar results were found with the darapladib metabolites. Darapladib was highly plasma protein bound with 0.047% and 0.034% unbound circulating in plasma in severely renally impaired and healthy subjects, respectively. Unbound plasma darapladib exposures were more than two-fold higher in severely renally impaired subjects than in healthy controls. Adverse events (AE) were reported in 38% of healthy subjects and 75% of severely renally impaired subjects, most of which were mild or moderate in intensity.

Conclusions

The results of this study showed that darapladib exposure was increased in subjects with severe renal impairment compared with healthy controls. However, darapladib was generally well tolerated in both groups.     

The effects of renal impairment on the pharmacokinetics and safety of fosfluconazole and fluconazole following a single intravenous bolus injection of fosfluconazole

AIMS: Fosfluconazole is a phosphate prodrug of fluconazole (FLCZ). This study was conducted to investigate the effect of renal impairment on the pharmacokinetics of fosfluconazole and FLCZ, and to assess the safety and toleration of fosfluconazole following a single intravenous bolus injection of fosfluconazole in subjects with normal and impaired renal function. METHODS: In an open, parallel-group, two-centre study, subjects with normal and impaired renal function received a single 1000-mg bolus intravenous injection of fosfluconazole. Subjects were categorized as Normal (> 80 ml min(-1)), Mild (51-80 ml min(-1)), Moderate (30-50 ml min(-1)) or Severe (< 30 ml min(-1)) impairment group according to their Cockcroft and Gault creatinine clearance (CLcr) values. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 240 h and 48 h postdose, respectively. RESULTS: Fosfluconazole plasma concentrations were very similar across the four groups, and there was no apparent relationship between any of the fosfluconazole pharmacokinetic parameters with increasing renal impairment. The conversion of fosfluconazole to FLCZ was unaffected by the degree of renal impairment. Only small amounts of fosfluconazole were excreted in the urine suggesting almost complete conversion to FLCZ. FLCZ concentrations were still detected in plasma after 240 h postdose and remained higher at the later sampling times in subjects in the Moderate and Severe groups. The area under the plasma concentration vs. time curve between time zero and infinity (AUC), the terminal elimination phase half-life (t(1/2)) and the mean residence time (MRT) of FLCZ all increased with the degree of renal impairment. The ratios (95% confidence interval) for AUC (Renal impairment group/Normal group) were 112.8% (89.5, 142.1), 240.6% (128.2, 451.4) and 355.1% (259.3, 486.3) for the Mild, Moderate and Severe impairment groups, respectively. There was a linear relationship between CLcr with AUC, t(1/2), MRT and the total plasma clearance of FLCZ (CL/F). Both the amount excreted over 48 h in the urine and the renal clearance of FLCZ decreased with an increase in renal impairment. The adverse events reported were mild to moderate in intensity, and there was no observed relationship with impairment group. There were no severe or serious adverse events, and in general fosfluconazole was well tolerated. CONCLUSIONS: The pharmacokinetics of fosfluconazole, including its efficient conversion into FLCZ, were unaffected by renal impairment. For FLCZ, there was a significant linear relationship between CLcr and AUC, t(1/2), MRT and CL/F, with AUC, t(1/2) and MRT increasing and CL/F decreasing as renal impairment increased. The dose adjustment used for FLCZ (half normal dose for patients with CLcr at 相似文献   

Clinical pharmacological studies with the vasodilator endralazine in patients with renal impairment

Summary The influence of renal impairment on the pharmacokinetics of endralazine was studied in 12 patients; 4 patients on regular haemodialysis therapy (creatinine clearance less than 5 ml/min) and 8 patients with varying degrees of renal impairment (creatinine clearance 11–52 ml/min). Following an oral dose of 10 mg endralazine the mean terminal elimination half-life (t_1/2) in the dialysis sub-group was prolonged at 7.1 h (range 3.3 to 14 h), compared to 3.6 h in the other renal patients (and compared to 2.3 h in hypertensive patients with normal renal function). After one week's therapy with 10 mg B.D. endralazine in the 8 patients with moderate renal impairment there was a significant increase in t_1/2 to 8.6 h but there was no significant change in the area under the drug concentration-time curve and no evidence of drug accumulation. In this study those patients with the poorest renal function had the longest t_1/2 after acute dosing. There was a significant correlation between creatinine clearance and acute t_1/2 but there was considerable variability in individual patients and, even with severe degrees of renal impairment, major dose adjustments do not appear necessary.     

Pharmacokinetics of oral acetyl-L-carnitine in renal impairment

Summary Acetyl-L-carnitine 1.5 g and 3.0 g was administered as three divided doses on each of two occasions to 24 people with varying renal failure (creatinine clearance 127 – 8 ml·min^–1). Plasma and urinary concentrations of total-L-carnitine, free (non-esterified) carnitine, short-chain esters and acetyl-L-carnitine were measured.The baseline (pre-study) concentrations of all four substances were related to renal function. Patients whose creatinine clearance was below about 30–40 ml·min^–1 were had the highest concentrations.Renal elimination of all four substances was related to dose and to renal function. There was evidence for dose-related elimination, with greater elimination of the larger dose.     

Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor

AIM

This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10 mg single dose), an oral, direct Factor Xa inhibitor.

METHODS

Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80 ml min⁻¹), mild (50–79 ml min⁻¹), moderate (30–49 ml min⁻¹) and severe impairment (<30 ml min⁻¹).

RESULTS

Renal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration–time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively.

CONCLUSIONS

Rivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.     

Pharmacokinetics of cefadroxil in patients with terminal renal impairment

The pharmacokinetics of cefadroxil were studied in 15 subjects divided into 3 groups: healthy volunteers, patients with terminal renal impairment in interdialysis sessions and patients with terminal renal impairment undergoing hemodialysis sessions.The serum levels of the antibiotic were determined by a microbiologic plate diffusion method using Bacillus subtilis (ATCC no. 6633) as the test organism.Renal impairment causes a decrease in the elimination rate of the antibiotic. The serum half-life has a value of 1.20 ± 0.21 h in the healthy volunteers, 26.56 ± 8.00h in patients in interdialysis periods and 2.45 ± 0.72 h in patients undergoing hemodialysis sessions.Hemodialysis partially restores absorption and elimination of cefadroxil to levels which approach those established in healthy volunteers.     

Pharmacokinetics of butorphanol nasal spray in patients with renal impairment

1The pharmacokinetics of butorphanol were evaluated in 18 female volunteers with varying degrees of renal function following a single, 1 mg transnasal dose of butorphanol tartrate. The creatinine clearance (CL_CR) values for subjects in the normal (NOR), moderately impaired (MI), and severely impaired (SI) groups were ≥70 ml min⁻¹, 30–60 ml min⁻¹, and ≤30 ml min⁻¹, respectively. 2Serial blood and urine samples were collected immediately after dosing for 48 h. Plasma concentrations of butorphanol were determined using a specific radioimmunoassay. Urine concentrations of butorphanol and its metabolites (hydroxy-butorphanol, norbutorphanol and their glucuronide conjugates) were determined using h.p.l.c. with fluorescence detection. 3There was no significant difference between the three treatments for peak plasma concentration of butorphanol and time to peak. Statistically significant differences were detected among the study groups for AUC, t_1/2, MRT, and CL_R with the mean values for severely impaired subjects significantly different from those of normal renal subjects; mean values for moderately impaired subjects were not significantly different from either the normal or severely impaired groups for all respective parameters. 4The elimination half-life of butorphanol increased from 5.75 h in NOR to 10.48 h in SI. A similar trend was observed for MRT. Creatinine clearance (CL_CR) significantly correlated with CL_R (r=0.563, P=0.019), CL_T/F (r=0.505, P=0.033), t_1/2 (r=−0.554, P=0.017) and λ (r=0.606, P=0.008). 5Although the exposure of butorphanol was greater in subjects with renal impairment, there was no trend for an increase in the number of adverse experiences reported by subjects with renal dysfunction. 6Patients with less than 30 ml min⁻¹ creatinine clearance may require less frequent administration of transnasal butorphanol as compared with subjects with normal or moderately impaired renal function.     

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.