What factors need to be considered when dosing patients with renal impairment?
Yüklə 73,86 Kb.
|
- Bu səhifədəki naviqasiya:
- What factors need to be considered when dosing patients with renal impairment
- Answer General drug dosing guidance in renal impairment
- Absorption and bioavailability
- Measuring renal function
- Limitations
- Quality Assurance Prepared by
|
Medicines Q&As  
 Q&A 167.6
What factors need to be considered when dosing patients with renal impairment? Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp Date prepared: 18th February 2016 Background Many commonly used drugs or their metabolites are excreted by the kidney, and this has particular significance for people with renal impairment (RI). Impaired renal function alters drug pharmacokinetics, potentially changing drug efficacy and increasing the likelihood of unwanted effects, including renal toxicity (1). There may also be pharmacodynamic changes (2). Answer General drug dosing guidance in renal impairment Drugs, or their metabolites, that are mainly excreted by the kidney may have a prolonged half-life in RI, and accumulation sufficient to be of clinical concern occurs in patients with RI if ≥30% of the drug is eliminated unchanged in the urine or if the drug has active or toxic metabolites which are renally excreted. Dose reduction needs to be considered, depending on the degree of RI and fraction of drug excreted unchanged in order to avoid potential toxicity (3, 4, 5, 6). Single doses are not thought to be dangerous as accumulation is unlikely (3). If a drug has a narrow therapeutic index with no potential for monitoring, potential renal adverse effects, or serious dose-related adverse effects, an alternative should be found, if possible. In addition, caution should be exercised in patients with severe hepatic dysfunction, which is usually accompanied by some RI ('hepato-renal syndrome')(3). There are three approaches to altering drug maintenance doses in patients with RI, depending on the desired goal of therapy (1,5,7):
Drugs that require maintenance of a serum concentration over the dosing interval should be administered at the usual intervals, but with reduced doses. Drugs for which specific peak serum concentrations must be achieved will be dosed with the standard dose at extended intervals (8). In general, the latter approach will achieve similar peak and trough concentrations and AUC to those in patients with normal renal function (9). Drugs with a narrow therapeutic index (e.g. vancomycin, lithium) require the greatest care in use (3). Careful monitoring of plasma levels and clinical response are needed, followed by dose adjustments, if appropriate. When a rapid therapeutic response is needed, a loading dose may even be needed if one was not routinely recommended for patients with normal renal function (9). The loading dose may be calculated by the following formula: patient’s loading dose= usual loading dose x [(patient’s VD)/(normal VD)](9). The plasma half-life of drugs excreted by the kidney is prolonged in RI and it takes about five times the half-life of a drug to reach steady state concentrations, therefore it can take many doses for the reduced dosage to achieve a therapeutic plasma concentration(10). Consequently, the initial dose/s of a course of a critical medicine e.g. an antibiotic should not be reduced because otherwise it may take a long time to reach therapeutic levels. Pharmacokinetics The absorption, distribution, metabolism and excretion of drugs can be affected by RI to varying degrees (2, 3, 7). These will be discussed individually.
Absorption (proportion of drug absorbed from the gastrointestinal tract) and bioavailability (the proportion of the administered dose which reaches the systemic circulation of the patient) can both be affected in renally impaired patients. Absorption may be reduced due to a number of factors such as nausea, vomiting or diarrhoea associated with uraemia and gut oedema. An increase in the gut pH from increased gastric ammonia production in uraemia, or from co-administered drugs, reduces the bioavailability of drugs requiring an acidic environment for absorption. The increase in pH may increase the bioavailability of weakly acidic drugs (2). The effect of CKD on intestinal cytochrome P 450 metabolic enzymes and transporters may lead to an increase in bioavailability of orally administered drugs, e.g. tacrolimus, in these patients (11). Drug doses are not routinely altered to allow for these factors alone, but a change in dose or route of administration may be considered if the desired therapeutic effect is not being achieved (2).
The state of hydration of a patient will affect the volume of distribution (Vd) of water soluble drugs with a small Vd e.g. aminoglycosides with a Vd of approximately 0.25L/kg (2, 8). In patients with conditions such as sepsis, major burn injury etc., oedema formation and administration of IV fluids leads to an increase in total body water thus increasing the VD of hydrophilic antimicrobials. Adequate loading doses are therefore essential. In critically ill patients with associated acute kidney injury (AKI) the loading dose of hydrophilic antimicrobials e.g. beta-lactams, aminoglycosides, may even need to be increased by up to 25-50% (9,12). Conversely dehydration or muscle wasting may result in unexpectedly high concentrations of drugs(13). Another factor affecting Vd in patients with CKD is reduction in protein binding(Pb), caused by decreased serum albumin concentrations, reduction in albumin affinity for drugs and competition for binding sites from accumulated metabolites and endogenous substances. This is clinically important for highly protein bound drugs (>80%) (2,4,8). Apparently low total plasma concentrations of these drugs will still be therapeutic as the proportion of free, therefore active, drug will be higher. An important example of this is phenytoin (2,4 8). Alterations in tissue binding may also affect the Vd of a drug (2). For example, the Vd of digoxin is decreased in patients with severe RI, probably due to a decreased in tissue binding (5,6). However changes to distribution (Pb and Vd) are most likely to be a significant issue in renal replacement therapies (refer to Q&A168.7) Metabolism Renal impairment affects the metabolism of drugs (4) e.g. reduction and hydrolysis are slower. This may increase serum concentrations of the parent drug and consequent toxicity if the drug is metabolised to inactive metabolites (2). Many drugs and/or their phase I metabolites are eliminated by glucuronidation and the glucuronides are excreted by renal mechanisms. Therefore in patients with RI, glucuronide conjugates will accumulate in the plasma. For some drugs, e.g. ketoprofen, systemic hydrolysis of the glucuronide will occur, leading to increased levels of the parent compound ( 5,6). Many studies have also shown reduced acetylation in patients with RI (11). Many active or toxic metabolites depend on renal function for elimination; therefore they may accumulate in RI, for example norpethidine following the administration of pethidine (2,14). Norpethidine is a central nervous system stimulant but not an analgesic. Even in patients with mild RI, such as elderly patients, this metabolite can reach sufficient concentrations to cause seizures. The use of lower doses of pethidine may limit its efficacy, therefore alternative analgesics should be considered (5). There is also clinical evidence that alterations in hepatic drug metabolism and transport occur during acute and chronic renal failure (14,15). In patients with severe chronic RI the accumulation of uraemic toxins and inflammatory cytokines affects the activity of cytochrome P 450 metabolic enzymes and of P-glycoprotein, organic anion-transporting peptides and multidrug resistance-associated protein transporters in the liver and gastro-intestinal tract (11,15). Drugs affected include imipenem, meropenem, vancomycin(14), digoxin and erythromycin (11). For example, uraemic toxins inhibit organic-anion-transporting polypeptide (OATP)-mediated uptake of erythromycin into hepatocytes, which may be responsible for its reduced hepatic clearance in severe CKD (11). Studies have shown that non-renal clearance of these drugs is lower in patients with acute RI and lowest in patients with chronic RI, compared with patients with normal renal function (14). Even drugs such as lidocaine which is mostly metabolized by hepatic CYP1A2 and CYP3A4 have been reported to have reduced clearance and prolonged half-life in patients with CKD, compared with control subjects (11). The determination of specific drug-metabolising enzymes and transporters that are affected by RI is complicated because of i) the interactions between them, ii) apparent differential effects in the intestine and liver, iii) as yet incomplete understanding of the effect of uraemia on metabolism mediators. This makes it difficult to translate pharmacokinetic data into clinically useful drug dosing recommendations. Pharmacokinetic studies in patients with RI should be performed for all drugs, even those primarily cleared by the liver(16). Careful monitoring of patients is therefore essential. Excretion The extent to which a reduction in glomerular filtration is important for the elimination of a drug depends on the proportion of the administered drug or any active or toxic metabolites which are eliminated by the kidney (2). For some drugs, e.g. methotrexate, reduction of renal excretion in patients with advanced CKD is thought to occur also through a competitive inhibition of renal transporter proteins by uraemic toxins (11). The excretion of several other drugs mainly eliminated in the urine by active tubular secretion, is also reduced in RI e.g. sitagliptin and varenicline. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. However the clinical relevance of hOAT-3 in sitagliptin transport has not been established(17). A small number of drugs (for example, carbamazepine, theophylline) are mainly excreted hepatically without toxic metabolites. The effect of RI on their metabolism has not yet been fully studied, but appears to be unaffected by RI in humans (14,15). Monitoring of efficacy, blood levels or adverse events is advisable however, in view of the emerging data on the effect of CKD on drug metabolism (3,11). The effects of a number of drugs are measured by direct physiological response. These drugs can be used, with caution (i.e. lower starting doses), in renally impaired patients. Indeed many of the drugs used to manage renal failure (e.g. calcitriol, phosphate binders) are titrated according to response (3). Pharmacodynamics Uraemia in RI can alter the clinical response to certain drugs (2,18) for example;
Measuring renal function Accurate measurement of renal function is essential in patients with RI so that drug dosages can be adjusted accordingly. Because the production and excretion of creatinine decline with age, normal serum creatinine values may not represent normal renal function in older patients (20).The normal process of ageing involves the loss of nephrons and therefore it is reasonable to assume that all elderly patients have some degree of renal impairment (21). Current NICE guidance recommends the use of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation to estimate GFR or the use of equations incorporating an alternative marker – cystatin C (22). However the estimation of glomerular filtration rate (eGFR) provided by the Modification of Diet in Renal Disease trial (MDRD) has been the most widely used method of estimating renal function (23). Estimates of eGFR calculated using creatinine-based equations become less accurate as true GFR increases (24), although the CKD-EPI equation is more accurate for values of GFR >60mL/min(26). In individuals with reduced body size or muscle mass, e.g. frail, elderly, critically ill or patients with cancer or muscle wasting diseases the use of creatinine-based equations will lead to an overestimation of the CrCl (21). Neither equation should be used in pregnant patients, children under 18 years, marked catabolism or rapidly changing renal function (10,21). Estimating CrCl from a serum creatinine level assumes that renal function is stable over several days or more (21) and that the serum creatinine level is fairly constant. With rapidly changing renal function the serum creatinine levels will no longer reflect the true creatinine clearance rate. Drug dosing calculations for patients with RI have traditionally been based on estimations of CrCl using Cockcroft & Gault (C&G) (18) and the vast majority of published drug dosing information is based on C&G estimation of CrCl (7). Despite this, advice on adjustment of drug doses in RI in the BNF is now expressed in terms of eGFR, rather than CrCl, for most drugs (10). Although the two measures of renal function are not interchangeable, the BNF advises that in practice, for most drugs and for most patients (over 18 years) of average build and height, eGFR (MDRD ‘formula’) can be used to determine dosage adjustments in place of CrCl (10). The national Kidney Disease Education Program in the USA has also endorsed the use of eGFR for drug dosing in renal disease (25,26). However, for potentially toxic drugs with a narrow therapeutic index, CrCl (calculated from the C&G formula) should be used to adjust drug dosages in addition to plasma-drug concentration and clinical response (10). The eGFR calculated by the MDRD equation is normalised to a standard body surface area (BSA) of 1.73m2.Therefore there is a potential for under- or over- dosing patients at extremes of body weight. In order to calculate the correct dose the normalised eGFR should be converted to the patient’s absolute GFR using the following formula: GFR ABSOLUTE = (eGFR x BSA ACTUAL/1.73) (10). Failure to correct to absolute, non-normalised GFR in patients with a BSA smaller than 1.73m2 will overestimate GFR and potentially result in drug overdosing. Conversely, in patients with a BSA greater than 1.73m2 this will underestimate GFR and will potentially result in drug under-dosing (7,18). The BNF advises that in patients at both extremes of weight (BMI of less than 18.5 kg/m2 or greater than 30 kg/m2) the absolute GFR or CrCl (calculated from the C&G formula) should be used to adjust drug dosages (10).When using the C&G equation to calculate CrCl it is important to note that it uses body weight as a marker of muscle mass (creatinine being a breakdown product of muscle). Therefore in obese or extremely underweight patients there is also potential for over- or under- estimation of CrCl. Guidance is available on when to use actual or ideal body weight in these circumstances (18). In general, ideal body weight (IBW) should be used when calculating C&G particularly in oedematous patients and patients with ascites. For obese patients IBW can be used, but some experts have suggested that an adjustment factor of 40% be applied to the patient’s excess weight over their ideal weight i.e. adjusted body weight = [IBW + (0.4x ABW-IBW)] where ABW is actual body weight (21,27).Clinical judgement is needed, e.g. if a patient's excess weight is due to high muscle mass not excess body fat, actual body weight should be used. Some experts have proposed the use of CrCl range for drug dosing purposes, with the lower boundary defined by using IBW in the CG equation and the upper boundary by using TBW(28). Where an accurate GFR is deemed necessary e.g. in chemotherapy dosing, an isotope GFR determination should be performed (7). There is evidence that in elderly patients with CKD the use of the MDRD equation to calculate eGFR instead of an estimated CrCl overestimates GFR and leads to the calculation of higher than recommended doses of drugs such as enoxaparin, gentamicin, digoxin, amantadine, gabapentin, NOACs and ramipril in up to 50% of these patients(29,30,31,32). For example, a general-practice based study in over 4100 patients with atrial fibrillation has shown that using MDRD instead of C&G to calculate eligibility and dose of dabigatran or rivaroxaban would have led to up to 15% of patients aged ≥ 80 being incorrectly judged eligible or receiving too high a dose of dabigatran. The corresponding figure for all patients taking rivaroxaban was 13.5% (33). The situation may be further complicated by the use of alternative equations to estimate GFR such as the CKD-EPI equation or the use of equations incorporating cystatin-C (22,34). In a study comparing 3 equations for estimating GFR in patients undergoing percutaneous coronary intervention (PCI), there was considerable discrepancy in the classification of patients into stages of CKD. The equations used were C&G, CKD-EPI and MDRD. Equation choice affected drug-dosing recommendations for antiplatelet and antithrombotic agents, with the formulas agreeing for only 34% of patients with a GFR of <30mL/min/1.73m2 (as estimated by at least one equation). The authors comment that the eGFR equation selected to determine drug dosing in the clinic ideally would be identical to the equation used in the drug’s original pharmacokinetic study; although many pharmacokinetic studies have used the C&G equation there is no standard approach (35). For new drugs most studies are designed and performed by the manufacturer therefore the manufacturer's dosage in RI recommendations should be followed. A study comparing secondary sources of prescribing information for patients with RI found a considerable degree of variability amongst the definitions and recommendations in four different standard sources (36,37). It is also worth noting that historically, there has been substantial variability in serum creatinine values reported by different clinical laboratory creatinine measurement methods. Consequently, the results of pharmacokinetic studies on which this dosing information was based, were dependent upon the particular method for measuring serum creatinine used in a given study (9,26). However it is not possible or practical to repeat all the studies using a standardised creatinine measurement method. The estimated GFR based on current standardised creatinine assays is likely to lead to different dosage recommendations from those intended by the original study, even if the same estimating equation is used, because of the change in analytical methodology (9,21). In addition the level of RI is often defined differently among the pharmacokinetic studies and each category (‘mild’, ‘moderate’, ‘severe’) often encompasses a broad range of kidney function. The drug dosage adjustment recommendations that use broad ranges of kidney function may not be optimal for all patients whose kidney function lies within the specified range, especially for drugs that have a narrow therapeutic index (9). For these reasons clinical judgement should be used alongside any estimates derived from equations (21). Acute Kidney Injury Patients with acute kidney injury (AKI) will often develop multiorgan dysfunction syndrome or multisystem organ failure. When dosing patients with AKI, these and other factors - rapidly fluctuating levels of renal function, changes in volume status and the effects of renal replacement therapy (RRT) - need to be considered in addition to those discussed above(9). Dosage adjustment should be guided by clinical judgement and monitoring, in addition to published guidance which may be based on older studies in CKD patients or patients on RRT. Refer to Q&A168.7. Volume status will affect the size of the loading dose of water-soluble antimicrobials (see above under 'Distribution'). For subsequent doses, the dose or dose interval is adjusted according to whether the antimicrobial effect is concentration- or time- dependent or both concentration- and time-dependent (12,38) (please refer to Blot et al. (12), Keller et al. (38) and Fissell (39) for a discussion of the pharmacodynamics and pharmacokinetics of antimicrobials in RI, AKI and renal replacement therapy[RRT]). Summary
Limitations This Q&A discusses general principles of drug dosage adjustment in adults. For information on dose adjustment of specific drugs or information on drug dosage adjustment in children, please consult the latest BNF, BNF for children, SPC and specialist sources of information (40). References 1() Consumers Association. The patient, the drug and the kidney. Drug and Therapeutics Bulletin 2006; 44 (12): 89-95. 2() Millsop A. Drug Dosing in patients with renal impairment and during renal replacement therapy. In: Ashley C, Morlidge C, editors. Introduction to renal therapeutics. London: Pharmaceutical Press; 2008. p. 127-137. 3() Sexton J. Drug use and dosing in the renally impaired adult. Pharmaceutical Journal 2003; 271: 744-746. 4() Aronoff GR et al. Drug Prescribing in Renal Failure. Dosing Guidelines for Adults and Children. 5th ed. Philadelphia: American College of Physicians; 2007. p.1-10 5() Brater DC. Drug dosing in patients with impaired renal function. Clin Pharmacol Ther 2009; 86: 483-9 6() Verbeeck RK and Musuamba F. Pharmacokinetics and dosage adjustment in patients with renal dysfunction. Eur J Clin Pharmacol 2009; 65:757-73 7() Ashley C, Currie A. editors. Renal Drug Handbook. 4th Edition 2014. Radcliffe Publishing Ltd. p. xiii – xvi 8() Churchwell MD, Mueller BA. Selected pharmacokinetic issues in patients with chronic kidney disease. Blood Purif 2007;25: 133-38 9() Matzke GR et al. Drug dosing consideration in patients with acute and chronic kidney disease – a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney International 2011; 80: 1122-37 10() Joint Formulary Committee. British National Formulary. November 2015. London: BMJ Group and Pharmaceutical Press; 2015, Prescribing in renal impairment. http://www.evidence.nhs.uk/formulary/bnf/current Accessed 03/12/15 11() Naud J et al. Current understanding of drug disposition in kidney disease. J Clin Pharmacol 2012;52: 10S-22S 12() Blot SI et al. The effect of pathophysiology on pharmacokinetics in the critically ill patient – concepts appraised by the example of antimicrobial agents. Adv. Drug Delivery Rev 2014; 77: 3-11 13() Wills S, Badiani A, Power J. Southampton Medicines Advice Service. Medicines Learning Portal. Clinical topics. Medicines and the kidney. Last updated: Sunday, July 12, 2015. Accessed via: http://www.medicineslearningportal.org/2015/07/medicines-and-kidneys.html on 02.12.15. 14() Vilay AM et al. Clinical review: Drug metabolism and nonrenal clearance in acute kidney injury. Critical Care 2008; 2008;12:235 15() Nolin T. Altered nonrenal drug clearance in ESRD. Curr Opin Nephrol Hypertens 2008; 17:555-9 16() Lalande L et al. Consequences of renal failure on non-renal clearance of drugs. Clin Pharmacokin 2014 53: 521-32 17() MSD Summary of Product Characteristics JANUVIA 25mg, 50mg, 100mg film-coated tablets. DORT 28th January 2016 . Accessed via http://www.medicines.org.uk/emc/medicine/19609/SPC/JANUVIA+25mg%2c+50mg%2c+100mg+film-coated+tablets/ on 18.2.16 18() Brown C. Prescribing principles for patients with chronic kidney disease. Pharmacy in Practice January/February 2008.p.23-27 http://www.pharmacyinpractice.com/past-issues/2008-volume-18-issue-1/7-PIP-Therapeutic-options-Jan-Feb-08.pdf 19() Nolin TD et al. Optimizing drug development and use in patients with kidney disease. J Clin Pharmacol 2011;51: 628- 30 20() Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician 2007;75:1487-96 21() Wills S, Badiani A, Power J. Southampton Medicines Advice Service. Medicines Learning Portal. Clinical topics. Assessing renal function. Last updated: Sunday, July 12, 2015. Accessed via: http://www.medicineslearningportal.org/2015/07/assessing-renal-function.html on 02.12.15. 22() National Institute for Health and Care Excellence. Clinical Guideline. Chronic kidney disease in adults: assessment and management. 23 July 2014. CG182. Accessed via http://www.nice.org.uk/guidance/cg182/ on 03.12.15 23() UK e CKD Guide. Revised January 2009. Renal Association. Available at http://www.renal.org/whatwedo/InformationResources/CKDeGUIDE.aspx accessed 18.2.16 24() BMA and NHS Employers. Chronic kidney disease frequently asked questions January 2010. Accessed via http://www.britishrenal.org/getattachment/CKD-Forum/Clinical-Managment/CKD-FAQs-(DH-Jan-2010).pdf.aspx on 18.2.16 25() Stevens LA et al. Comparison of drug dosing recommendations based on measured GFR and kidney function estimating equations. Am J Kidney Dis 2009; 54: 33-42 26() National Institute of Diabetes and Kidney and Digestive Diseases & National Kidney Disease Education Program. CKD and drug dosing: information for providers. Revised April 2015. http://www.nkdep.nih.gov/resources/CKD-drug-dosing.shtml#suggested-approach accessed on 16.2.16 27() Drug Dosing in Obesity Reference Table. Accessed via http://clincalc.com/Kinetics/ObesityDosing.aspx#AdjustedBW on 22.01.16 28() Brown DL et al. Functional range of creatinine clearance for renal drug dosing; a practical solution to the controversy of which weight to use in the Cockcroft-Gault equation. Ann Pharmacother 2013; 47: 1039-44 29() Denetclaw TH et al. Dofetilide dose calculation errors in elderly associated with use of the modification of diet in renal disease equation. Ann Pharmacother 2011; 45: e44 30() Gill J , Malyuk R , Djurdjev O et al. Use of GFR equations to adjust drug doses in an elderly multi-ethnic group-a cautionary tale. Nephrol Dial Transplant 2007; 22: 2894-99 31() Hellden A et al. Development of a computerised decisions support system for renal risk drugs targeting primary healthcare. BMJ Open 2015; 5: e006775 32() Cabello-Muriel A et al. Influence of equation used to estimate the renal function in dosage potentially nephrotoxic drug. Eur J Hosp Pharm 2015; 22:23-27 33() MacCallum PK, Mathur R, Hull SA et al. Patient safety and estimation of renal function in patients prescribed new oral anticoagulants for stroke prevention n atrial fibrillation; a cross-sectional study. BMJ Open 2013;3:e003343. Doi:10.1136/bmjopen-2013-003343 34() Lamb EJ, Stevens PE, Deeks JJ. What is the best glomerular filtration marker to identify people with chronic kidney disease most likely to have poor outcomes? BMJ 2015;350:g7667 (Published 12 January 2015) Accessed via http://www.bmj.com/content/350/bmj.g7667 on 03.12.15 35() Parsh J et al. choice of estimated glomerular filtration rate equation impacts drug-dosing recommendations and risk stratification in patients with chronic kidney disease undergoing percutaneous coronary interventions. J Am Coll Cardiol 2015; 65: 2714–23 36() Vidal L et al. Systematic comparison of four sources of drug information regarding dose adjustment of dose for renal function. Brit Med J 2005; 331: 263-6 37() Mehta DK et al. Dose adjustment in renal impairment. Brit Med J 2005; 331: 291-4 38() Keller F et al. Pharmacokinetic and pharmacodynamic considerations of antimicrobial drug therapy in cancer patients with kidney dysfunction. World J Nephrol 2015; 4: 330-44 39() Fissell WH. Antimicrobial dosing in acute renal replacement. Adv Chron Kidn Dis 2013; 20:85-93 40() Rodieux F et al. Effect of kidney function on drug kinetics and dosing in neonates, infants, and children. Clin Pharmacokinet (2015) 54:1183–1204 Quality Assurance Prepared by Julia Kuczynska, South West Medicines Information and Training, Bristol, (based on earlier work by Richard Cattell and Caroline Metters) Date Prepared 18th February 2016 Checked by Trevor Beswick, Director, South West Medicines Information and Training Date of check 30th March 2016 Search strategy
Available through NICE Evidence Search at www.evidence.nhs.uk Yüklə 73,86 Kb. Dostları ilə paylaş:
|